Fibrinogen receptor antagonists and their use

ABSTRACT

This invention relates to novel fused bicyclic compounds of the general formula (I): 
     
       
         
         
             
             
         
       
     
     wherein
 
the symbols are defined herein, to pharmaceutical compositions containing the compounds, processes for preparing the compounds, and to methods of using the compounds, alone or in combination with other therapeutic agents. The compounds are antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex, and are therefore useful for the inhibition of platelet aggregation, and for the treatment of thrombotic diseases and other diseases.

FIELD OF THE INVENTION

The present invention relates to novel compounds, which are antagonistsof fibrinogen receptors (FRAs), to pharmaceutical preparationscomprising them, to processes for their preparation, and to their use asactive ingredients in pharmaceuticals, alone or in combination withother therapeutic agents, in particular for the inhibition of plateletaggregation and for the treatment of thrombotic disorders.

BACKGROUND OF THE INVENTION

Platelets are cell-like anucleated fragments, found in the blood of allmammals that support primary hemostasis by forming hemostatic plugs atsites of vascular injury. Thrombosis is the pathological conditionwherein improper activity of the hemostatic mechanism results inintravascular thrombus formation. Activation of platelets and theresulting platelet aggregation has been associated with a variety ofpathophysiological conditions including cardiovascular andcerebrovascular thromboembolic disorders, for example, thethromboembolic disorders associated with unstable angina, myocardialinfarction, transient ischemic attack, stroke, thrombotic disorders suchas peripheral arterial disease, and diabetes.

Glycoprotein IIb/IIIa receptors (hereinafter referred to as GP IIb/IIIareceptors) are found on the surface of platelets and belong to asuperfamily of adhesion receptors known as integrins, which are composedof transmembrane glycoproteins containing α and β subunits. Fibrinogen,fibronectin, vitronectin and von Willebrand factor (vWF) are proteinsthat bind to and crosslink GP IIb/IIIa receptors on adjacent activatedplatelets and thereby effect aggregation of platelets.

The binding of fibrinogen is mediated in part by theArginine-Glycine-Aspartic acid (RGD) recognition sequence which iscommon to the adhesive proteins that bind GP IIb/IIIa receptors(Ferguson, J. J. and Zaqqa, M., Drugs, 1999, 58, 965-982; Mousa, S. Aand Bennett, J. S., Drugs of the future 1996, 21, 1141-1154; Ojima, I.,Chakravarty, S, and Dong, Q., Bioorganic and Medicinal Chemistry 1995,3, 337-360).

Platelets are activated by a number of agonists that include adenosinediphosphate (ADP), thrombin, serotonin, arachidonic acid, collagen andadrenaline among others, which are released in the body as a result ofvarious physiological reactions. Regardless of the nature of the stimuliinvolved in the activation of platelets, the final step of plateletaggregation is the binding of fibrinogen to the activated GP IIb/IIIareceptors on the surface of platelets thereby cross-linking platelets.(J. Leflcovits, E. F. Plow, E. J. Topol 1995, New England Journal ofMedicine, 332, 1553-1559). This makes GP IIb/IIIa receptors idealtargets for inhibiting platelet aggregation. The development of GPIIb/IIIa receptor antagonists would, therefore, provide an effectivestrategy for the control of platelet aggregation and hence thrombiformation (Bennett, J. S, Annual Reviews of Medicine, 2001, 52,161-184).

Cardiovascular diseases are among those that cause the highest mortalitythroughout the world. Thus, in order to prevent the cardiovasculardiseases caused by platelet aggregation, there is an increased necessityfor efficient anti-platelet aggregating treatment with drugs possessingspecific characteristics namely efficacy, negligible side effects andfast onset of action.

Current antiplatelet drugs are effective against only one type ofagonist; these include aspirin, which acts against arachidonic acid;ticlopidine, which acts against ADP; and hirudin, which acts againstthrombin.

Until recently, aspirin has been widely used as an inhibitor of plateletfunction (New England Journal of Medicine, 1994, 330, 1287). While thebenefits of aspirin have been demonstrated, there are clinicallimitations of this drug. These limitations have provided the impetusfor the development of newer antithrombotic agents having therapeuticadvantages over aspirin.

Ticlopidine, a thienopyridine derivative, has also been effectively usedin patients suffering cardiovascular diseases. However, this drug isassociated with a number of serious side effects.

Recently, a common pathway for all known agonists has been identified,namely the platelet GP IIb/IIIa complex, which is the membrane proteinmediating platelet aggregation (Phillips et al. Cell 1991, 65, 359-362).The development of GP IIb/IIIa receptor antagonists represents apromising new approach for antiplatelet therapy.

A fibrinogen receptor antagonist (hereinafter referred to as FRA) is anagent that inhibits the binding of fibrinogen to the platelet boundfibrinogen receptor GP IIb/IIIa and thereby prevents plateletaggregation and thrombus formation. Inhibition of platelet aggregationis a major target for the prevention and treatment of cardiovasculardiseases.

Known fibrinogen receptor antagonists are:

1. Monoclonal antibodies—e.g. abciximab2. Parenteral compounds

-   -   a) Synthetic peptides—e.g. eptifibatide    -   b) Non peptide peptidomimetics—e.g. tirofiban        3. Oral compounds—e.g. roxifiban, gantofiban

1. Monoclonal Antibodies:

In 1985, a mouse monoclonal antibody against GP known as c7E3, wasgenerated. Subsequently, the Fab fragment of a chimeric human-mousegenetic reconstruction of c7E3 (c7E3 Fab), known as abciximab, was usedin clinical trials (Drugs of the Future, 1995, 20, 457-463). Abciximabwas launched in 1995 on the US market, as an intravenous preparation.

2. Parenteral Compounds:

a) Eptifibatide, a synthetic cyclic peptide (J. Med. Chemistry, 2000,43, 3453-3473) was designed as a mimic of a snake venom peptide namelybarbourin. Eptifibatide is effectively used for the inhibition ofplatelet aggregation.b) Based on the observation that peptides containing the tripeptideArginine-Glycine-Aspartic acid (RGD) sequence function as fibrinogenreceptor antagonists, scientists attempted the development ofnon-peptide peptidomimetics as inhibitors of platelet aggregation(Hartman et. al. J. Med. Chemistry 1992, 35, 4640-4642).

A number of non-peptide fibrinogen receptor antagonists are known andare disclosed in the patents and other publications, which follow:

JP 10-017469 discloses oxyisoindole derivatives possessing fibrinogenreceptor antagonistic activity.EP-A-712844 discloses condensed ring carboxylic acid compounds havingplatelet GP IIb/IIIa receptor antagonist activity that are useful forthe prophylaxis and treatment of thrombotic diseases.EP-A-540334 discloses isoindolinone compounds as fibrinogen receptorantagonists, which are used in inhibiting the binding of fibrinogen toblood platelets and for inhibiting the aggregation of blood platelets.WO 96/26187 discloses a series of 3,4-dihydro-1(1H)-isoquinolinone basedcompounds as fibrinogen receptor antagonists useful for inhibitingplatelet aggregation with oral activity.Tirofiban, a non-peptide antagonist, developed by Merck & Co. is thefirst agent of this class to be used for the treatment of cardiovasculardiseases (Hartman G. D. et. al., J. Med. Chemistry, 1992, 35,4640-4642).U.S. Pat. No. 5,726,185 describes acetic acid derivatives useful for thetreatment or prophylaxis of illnesses which are caused by the binding ofadhesive proteins to blood platelets and by blood platelet aggregationand cell-cell adhesion.U.S. Pat. No. 5,378,712 describes N-acyl-alpha-aminocarboxylic acidderivatives and N-acyl-alpha-amino acid derivatives which are useful forthe treatment or control of illnesses which are caused by the binding ofadhesive proteins to blood platelets and by blood platelet aggregationand cell-cell adhesion.WO 93/07867 discloses substituted beta amino acid derivatives asplatelet aggregation inhibitors.

3. Oral Compounds:

There are currently no oral preparations on the market. Many compoundsthat had reached Phase III clinical trials had to be withdrawn due tolack of efficacy or adverse effects such as major bleeding episodes andthrombocytopenia.

EP-A-483667 describes cyclic imino derivatives having aggregationinhibiting effects.

WO 95/18619 describes bicyclic fibrinogen antagonists as inhibitors ofplatelet aggregation.

WO 95/14683 discloses isoxazolines and isoxazoles that are useful asantagonists of the platelet GP IIb/IIIa fibrinogen receptor complex forthe inhibition of platelet aggregation, as thrombolytics and/or for thetreatment of thromboembolic disorders.

Gantofiban is a platelet GPIIb/IIIa antagonist for the treatment ofvarious thrombotic diseases, such as acute coronary syndromes (J. Ganteet al. Bioorganic and Medicinal Chemistry letters, 1996, 6:20,2425-2430); Cromafiban is an orally active GP IIb/IIIa antagonist, whichwas being developed by COR Therapeutics as a potential treatment forthromboembolic disorders, acute coronary syndromes and stroke(Scarborough R. M., et. al, J. Med. Chemistry, 2000, 43:19, 3453-3473).

Even though several FRAs are described in the prior art, there is stilla need to develop specific agents having fibrinogen receptorantagonistic activity in the advent of the increased mortality rateamong patients suffering from cardiovascular diseases.

The FRAs currently available are all intravenous preparations, limitingtheir use to a hospital environment. A clear clinical need and marketexists for FRAs that can be administered by more patient-compliantroutes.

A focussed research on FRAs by the present inventors has resulted in thediscovery of novel compounds. These compounds are effective inhibitorsof GP IIb/IIIa receptors. Moreover, the compounds of the inventioninhibit GP IIb/IIIa receptors with an efficacy comparable to the knownFRAs, which are under clinical trials. Therefore, the compounds of thepresent invention are candidate agents for the treatment of thromboticdiseases.

SUMMARY OF INVENTION

As a result of the various studies made to solve the aforementionedproblems, the present invention provides compounds general formula (I)(as described hereinafter).

The present invention further provides processes for the preparation ofthe compounds of general formula (I) and intermediates thereof.

The present invention also provides pharmaceutical compositionscomprising as an active ingredient, compounds of the general formula(I), or pharmaceutically acceptable salts or prodrugs thereof, togetherwith a pharmaceutically acceptable carrier, diluent or vehicle.

The present invention further provides for the use of compounds of thegeneral formula (I), or pharmaceutically acceptable salts or prodrugsthereof for the manufacture of a medicament for the inhibition ofplatelet aggregation in a mammal.

Accordingly, the present compounds can be used for the prevention ortreatment of cardiovascular diseases, such as unstable angina,myocardial infarction and stroke, and thrombotic diseases in mammals,especially humans, where antagonism of the binding of fibrinogen to theplatelet membrane glycoprotein complex GP IIb/IIIa receptor is desired.

These and other objectives and advantages of the present invention willbe apparent to those skilled in the art from the following description.

BRIEF DESCRIPTION OF THE DRAWINGS OF THE INVENTION

Figures A to H, J and K represent schemes of preferred processes for thepreparation of example compounds of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses novel compounds that inhibit plateletaggregation. The compounds of the present invention are believed toinhibit the binding of fibrinogen to the platelet-bound fibrinogenreceptor GP MAIM and find use in antithrombotic therapies for diseasessuch as cardiovascular (arterial and/or venous) and cerebrovascularthromboembolic diseases.

The compounds of the present invention are compounds of the generalformula (I):

wherein:ring A is selected from: aryl and 5- or 6-membered heteroaryl;R^(A) is selected from: —NO₂, —(CH₂)pCN, —C(═O)—NR¹R², —C(═S)NR¹R²,—C(═NR¹)—SMe and —C(═NR¹)—OMe, orR^(A) is selected from one of the following groups of formula (2),formula (3) and formula (4):

wherein p is 0, 1, 2, 3, 4 or 5;s is 1, 2 or 3, and when s is 2 or 3 the groups R^(A) are independent ofeach other and can be the same or different;R¹ and R² are independently selected from: H, hydroxy, alkyl, partiallyor fully fluorinated alkyl, alkoxy, alkenyl, alkynyl, carboxy,—C(═O)OR⁵, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle;or R¹ and R², together with the nitrogen atom to which they areattached, form a saturated, partially saturated or aromatic heterocycle,optionally containing at least one additional hetero atom selected from:N, O and S;R³ and R⁴ are independently selected from: H, alkyl, partially or fullyfluorinated alkyl, alkenyl, alkynyl, —C(═O)OR⁵, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycle, —OR⁵, —SR⁵, —NR⁵R⁶,—S(═O)₂NR⁵R⁶, —S(═O)₂R⁵, —C(═O)R⁵, —C(═O)NR⁵R⁶, —C(═O)OR⁵, —C(═O)SR⁵,—OC(═O)R⁵, —OC(═O)OR⁵, —OC(═O)NR⁵R⁶, —OS(═O)₂R⁵, —S(C═O)NR⁵ and—OS(═O)₂NR⁵R⁶, or R³ and R¹ or R⁴, together with the respective nitrogenatoms to which they are attached, form an unsubstituted or substituted5-, 6- or 7-membered partially saturated or aromatic heterocycle,optionally having one or more additional heteroatoms selected from: N, Oand S, wherein the substituents are selected from: hydroxy, halogen,alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy and —C(═O)OR⁵;R⁵ and R⁶ are independently selected from: H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle, whereineach of said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkylalkylgroup optionally contains at least one hetero atom selected from: N, Sand O anywhere in the chain, including the terminal position;R⁷ and R⁹ have the same meaning as R³ and R⁴, defined above;R⁸ is selected from: H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl and heterocycle, wherein saidheterocycle is saturated, partially saturated or aromatic and containsat least one hetero atom selected from: N, O and S, with its point ofattachment either through C or N, and wherein each of said alkyl,alkenyl, alkynyl, cycloalkyl and cycloalkylalkyl groups optionallycontains at least one hetero atom selected from: N, O and S, anywhere inthe chain, including the terminal position;R^(B) is selected from: H, halogen, —CN, —NO₂, alkyl, partially or fullyfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycle, —NR¹⁰R¹¹, —OR¹⁰, —SR¹⁰, S(O)R¹⁰, S(O)₂R¹⁰,—NHC(═O)R¹⁰, —NHOR¹⁰, —OC(═O)R¹⁰, SC(═O)R¹⁰, —NHC(═O)OR¹⁰, —OC(═O)OR¹⁰,—C(═O)NR¹⁰R¹¹, —C(═O)R¹⁰, and —C(═O)OR¹⁰;R¹⁰ and R¹¹ have the same meaning as R⁵ or R⁶, defined above;s is 1, 2 or 3 and when s is 2 or 3 the groups R^(B) are independent ofeach other and can be same or different;Y¹ and Y² are independently selected from: H, R¹², R¹³, NR¹²R¹³, OR¹²,SR¹², CH₂(OR¹²), CH₂(SR¹²), CH₂S(═O)R¹² and CH₂S(═O)₂R¹², orY¹ and Y², together, are selected from: ═O, ═S, ═CR¹²R¹³, ═NR¹² and═N—OR¹²;R¹² and R¹³ are selected from: H, OR⁵, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl and aryl;

Z is CH or N;

W is (CH₂)_(u), wherein u is the integer 1 or 2;R^(C) is selected from: R⁵, ═O, ═NR¹⁴, ═S, CN, NR¹⁴R¹⁵, OR¹⁴, SR¹⁴,S(═O)₂R¹⁶ and COR¹⁶;R¹⁴ and R¹⁵ have the same meaning as R⁵ and R⁶, defined above;s is 1, 2 or 3 and when s is 2 or 3 the groups R^(C) are independent ofeach other and can be same or different;R¹⁶ is selected from: H, OR¹⁴, N(R¹⁴)₂, NR¹⁴R¹⁵, SR¹⁴ and R⁵, whereinR⁵, R¹⁴ and R¹⁵ are as defined above;n is 0, 1, 2, 3, 4 or 5;R^(D) and R^(E) are independently selected from: H and an unsubstitutedor substituted group selected from: alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl and heterocycle, wherein thesubstituents are selected from: hydroxy, halogen, alkyl, alkenyl,alkynyl, oxo, carboxy, —C(═O)OR⁵, —OR¹⁷, —SR¹⁷, —NR¹⁷R¹⁸, —NHC(═O)R¹⁷,—NHC(═O)OR¹⁷, —OC(═O)R¹⁷, —SC(═O)R¹⁷, —OS(═O)₂R¹⁷ and —NHS(═O)₂R¹⁷;R¹⁷ and R¹⁸ have the same meaning as R⁵ and R⁶, defined above;R^(F) is selected from: (H, H), (—H, —OH), O, S, N(OR¹⁹), N[OC(═O)OR¹⁹],N[OC(═O)R¹⁹] and N[OS(═O)₂NR¹⁹R²⁰];R¹⁹ and R²⁰ have the same meaning as R⁵ and R⁶, defined above;R^(G) is selected from: aryl, heteroaryl, and partially or fullysaturated heterocycle, where said aryl, heteroaryl and heterocycle aresubstituted in each case by one or more groups independently selectedfrom: —R⁵, halogen, —CN, —SCN, —CNO, —OR²¹, —OC(═O)R²¹, —OS(═O)₂R²¹,—OS(═O)₂NR²¹R²², —OC(═O)OR²¹, —OC(═O)SR²¹, —OC(═O)NR²¹R²², —SR²¹,—S(═O)R²¹, —SC(═O)H, —SC(═O)OR²¹, —NO₂, —NR²¹ (OR²²), —NR²¹R²²,—NR²¹C(═O)R²², —N(R²¹)C(═O)OR²², —N[S(═O)₂R²¹]R²³, C(═O)OR²¹,—S(═O)₂R²¹, —S(═O)₂OR²¹ and a group of formula (5):

T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5)

R²¹ and R²² have the same meaning as R¹ and R², defined above:T is selected from: —CH₂, O, S and NH;q is 0, 1, 2, 3, 4, 5 or 6;R²³ and R²⁴ are independently selected from: H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylallyl, aryl, arylalkyl, heterocycle and C(═O)R²⁵,wherein said alkyl and alkenyl optionally contain at least one heteroatom selected from: O, S and N, in any position of the alkyl or alkenylchain, and said alkyl and alkenyl are unsubstituted or substituted withat least one group selected from: —OR¹, —OC(═O)R¹, —OS(═O)₂R¹,—S(═O)₂NR¹R², —OC(═O)OR¹, —OC(═O)SR¹, —OC(═O)NR¹R², —SR¹, —S(═O)R¹,—SC(═O)H, —SC(═O)OR¹, —NR¹(OR²), —NR¹R², —NR¹C(═O)R², —N(R¹)C(═O)OR²,—NR¹S(═O)₂R², C(═O)OR¹, —S(═O)₂R¹ and —S(═O)₂OR¹;R²⁵ is selected from: OR⁵, SR⁵, —OCR³R⁴ and —NR⁵R⁶, wherein R³, R⁴, R⁵and R⁶ are as defined above and wherein, optionally, R³ and R⁴, togetherwith the carbon to which they are attached, form an unsubstituted orsubstituted 5-, 6- or 7-membered saturated, partially saturated oraromatic heterocycle having one or more heteroatoms selected from: N, Oand S, wherein the substituents are selected from: hydroxy, halogen,alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy and —C(═O)OR⁵; and thegroup NR⁵R⁶ is, optionally, a heterocycle containing at least oneadditional heteroatom selected from: O, S, and N;in all its stereoisomeric and tautomeric forms and mixtures thereof inall ratios, and its pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates and prodrugs.

In a first embodiment of the invention, there are provided novelcompounds of the general formula (I), or prodrugs, tautomeric forms,stereoisomers, pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates, or polymorphs thereof;

whereinring A is aryl;p is 0, 1 or 2;s is 1;Y¹ and Y², together, are selected from: ═O, ═S, ═CR¹²R¹³, ═NR¹² and═N—OR¹²;

Z is N;

R^(F) is selected from: (H, H), (H, OH), O and S;R^(G) is selected from: aryl, heteroaryl and partially or fullysaturated heterocycle, wherein said aryl, heteroaryl and heterocycle aresubstituted by one or more groups independently selected from: —R⁵,halogen, —CN, SCN, CNO, —OR²¹, —OC(═O)R²¹, —OS(═O)₂R²¹, —OS(═O)₂NR²¹R²²,—OC(═O)OR²¹, —OC(═O)SR²¹, —OC(═O)NR²¹R²², —SR²¹, —S(═O)R²¹, —NO₂,—NR²¹(OR²²), —NR²¹R²²—NR²¹C(═O)R²², —N(R²¹)C(═O)OR²², —N[S(═O)₂R²¹]R²³,—C(═O)OR²¹, —S(═O)₂R²¹, —S(═O)₂OR²¹ and a group of the formula (5);q is 0, 1, 2 or 3; andR¹-R¹⁸, R²¹-R²⁵, W, T, R^(B), R^(C), R^(D), R^(E) and n are as definedin general formula (I) above.

In a second embodiment of the invention, there are provided novelcompounds of the general formula (I), or prodrugs, tautomeric forms,stereoisomers, pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates or polymorphs thereof;

whereinring A is phenyl;p is 0, 1 or 2;s is 1;Y¹ and Y², together, are selected from: ═O and ═S;

Z is N;

R^(C) is selected from: H, alkyl, aryl, heterocycle, ═O, ═NR¹⁴, ═S, CN,NR¹⁴R¹⁵, OR¹⁴, SR¹⁴, S(═O)₂R¹⁶ and COR¹⁶;n is 0, 1, 2 or 3;R^(G) is selected from: aryl, heteroaryl and partially or fullysaturated heterocycle, wherein said aryl, heteroaryl and heterocycle aresubstituted by one or more groups of the formula (5) and, optionally,further substituted by one or more groups selected from: —R⁵, halogen,—CN, —SCN, —CNO, —OR²¹, —OC(═O)R²¹, —OS(═O)₂R²¹, —OS(═O)₂NR²¹R²²,—OC(═O)OR²¹, —OC(═O)SR²¹, —OC(═O)NR²¹R²², —SR²¹, —S(═O)R²¹, —NO₂,—NR²¹(OR²²), —NR²¹R²², —NR²¹C(═O)R²², —N(R²¹)C(═O)OR²², —N[S(O)₂R²¹]R²³,C(═O)OR²¹, —S(═O)₂R²¹ and —S(═O)₂OR²¹;q is 0, 1, 2 or 3; andR¹-R¹¹, R¹⁴-R²⁵, W, T, R^(A), R^(B), R^(D), R^(E), R^(F) and u are asdefined in general formula (I) above.

In a third embodiment of the invention, there are provided novelcompounds of the general formula (I), or prodrugs, tautomeric forms,stereoisomers, pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates or polymorphs thereof;

whereinring A is phenyl;R^(G) is selected from: phenyl, piperidinyl and piperazinyl, substitutedwith one or more groups selected from: a group of the formula (5),OCH₂Phenyl and —CH₂C(O)R²⁵, and, optionally, further substituted by oneor more groups selected from: —R⁵, halogen, —CN, —SCN, —CNO, —OR²¹,—OC(═O)R²¹, —OS(═O)₂R²¹, —OS(═O)₂NR²¹R²², —OC(═O)OR²¹, —OC(═O)SR²¹,—OC(═O)NR²¹R²², —SR²¹, —S(═O)R²¹, —SC(═O)H, —SC(═O)OR²¹, —NO₂,—NR²¹(OR²²), NR²¹R²², —NR²¹C(═O)R²², —N(R²¹)C(═O)OR²², —NR²¹S(═O)₂R²²,—N[S(═O)₂R²¹]R²³, C(═O)OR²¹, —S(═O)₂R²¹ and —S(═O)₂OR²¹;W is (CH₂)_(u), wherein u is 1; andR¹-R²⁵, T, Z, Y₁ and Y₂, R^(A), R^(B), R^(C), R^(D), R^(E), R^(F), n, s,p and q are as defined in general formula (I) above.

In a fourth embodiment of the invention, there are provided novelcompounds of the general formula (I), or prodrugs, tautomeric forms,stereoisomers, pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates or polymorphs thereof;

whereinR^(A) is a group of the formula (3);R₁ is hydrogen;R₃ and R₄ are independently selected from: H, OH, —C(O)OH and—C(O)Oalkyl;R^(B) ═R^(C)═R^(D) ═R^(E)=hydrogen;

Z is N;

Y¹ and Y², together are ═O;n is the integer 0 or 1;R^(G) is phenyl, substituted with one or more groups selected from:hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy,—C(═O)OR⁵, SR²¹, S(═O)₂R²¹, —N(R²¹)—C(O)CH₃, —CH₂C(O)R²⁵ and-T-(CH₂)_(q)—CH₂—C(O)R²⁵;q is 0, 1, 2 or 3;R²⁵ is selected from: OR⁵, OCR³R⁴ and NR⁵R⁶, wherein R³ and R⁴, togetherwith the carbon to which they are attached, form an unsubstituted orsubstituted 5-, 6- or 7-membered saturated, partially saturated oraromatic heterocycle having one or more heteroatoms selected from: N, Oand S, wherein the substituents are selected from: hydroxy, halogen,alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy, —C(D)OR⁵; andR⁵, R⁶ and R²¹ are independently selected from: H, alkyl and phenyl.W is (CH₂)_(u), wherein u is 1; andR³, R¹⁹, R²⁰, R²², R^(F), T, p and q are as defined in general formula(I) above.

In a fifth embodiment of the invention, there are provided novelcompounds of the general formula (I), or prodrugs, tautomeric forms,stereoisomers, pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates or polymorphs thereof;

whereinR^(A) is a group of the formula (3);R₁ is hydrogen;R₃ and R₄ are independently selected from: H, OH, —C(O)OH and—C(O)Oallyl;R^(B)═R^(C)═R^(D)═R^(E)=hydrogen;

Z is N;

Y¹ and Y², together are ═O;n is the integer 0 or 1;R^(G) is selected from: piperidinyl and piperazinyl, wherein saidpiperidinyl and piperazinyl are substituted with one or more groupsselected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo,carboxy, —C(═O)OR⁵ and -T-(CH₂)q-CH₂—C(O)R²⁵;q is 0, 1, 2 or 3;R²⁵ is OR⁵, wherein R⁵ is selected from: H, alkyl and phenyl; andR¹, R³-R⁶, T and p are as defined in general formula (I).

Yet other embodiments of the present invention provide processes for thepreparation of compounds of general formula (I), and their use as activeingredients in pharmaceuticals, alone or in combination with othertherapeutic agents, in particular for the inhibition of plateletaggregation and for the treatment of thrombotic disorders in mammals,especially humans.

Listed below are definitions of various terms used to describe thecompounds of the present invention. These definitions apply to the termsas they are used throughout the specification (unless they are otherwiselimited in specific instances) either individually or as part of alarger group. They should not be interpreted in the literal sense. Theyare not general definitions and are relevant only for this application.

The term “heterocycle” or “heterocyclic” can be defined as a stable J-7membered monocyclic or bicyclic, for example 7-10 membered bicyclic,ring which may be saturated, partially saturated or aromatic in nature.Besides carbon atoms, the ring contains 1-4 heteroatoms. The term“heteroatom” as used herein means an atom of any element other thancarbon or hydrogen. Preferred heteroatoms are nitrogen (N), oxygen (O),sulfur (S) and phosphorous (P). The atoms N and S can exist in oxidizedform and N can be quaternized. The terms “heterocycle” and“heterocyclic” include a bicyclic ring comprising a heterocyclic ring asdefined above fused to a benzene ring. The attachment of above definedheterocyclic ring to the main structure may be through a carbon atom ora heteroatom provided that a stable structure results.

The above defined heterocyclic ring may be substituted anywhere in thering provided that a stable structure is obtained. Examples of suchheterocycles include, but are not limited to, acridinyl, azocinyl,benzofuranyl, benzimidazolyl, benzothiophenyl, carbazolyl, chromenyl,chromenyl, cinnolinyl, decahydroquinolinyl, furanyl (furyl), furazanyl,imidazolyl, imidazolinyl, indolenyl, indolizinyl, indolyl, indolinyl,1H-indazolyl, isobenzofuranyl, isoindolinyl, isooxazolyl, isooxazolinyl,isoquinolinyl, isothiazolyl, morpholinyl, octahydroisoquinolinyl,oxazolidinyl, phenoxathinyl, phenazinyl, piperidinyl, piperazinyl,4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazolinyl, pyrazolyl,pyrazolidinyl, pyrazinyl, pyridyl (pyridinyl), pyrimidinyl, pyridazinyl,pyrrolyl, pyrrolidinyl, pyrrolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinazolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thiazolyl, triazinyl, thienyl,6H-1,2,5-thiadiazinyl and xanthenyl.

It should be noted that any heteroatom with unsatisfied valences isassumed to have the hydrogen atom to satisfy the valences.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine,chlorine or bromine.

As used herein, the term “alkyl” includes both branched and straightchain saturated aliphatic hydrocarbons having C₁-C₁₅ carbon atom(s),preferably C₁-C₁₂ carbon atom(s), most preferred C₁-C₆ carbon atom(s);examples of such groups include, but are not limited to, methyl, ethyl,propyl, butyl, isopentyl, neopentyl, and hexyl; the term “cycloalkyl” isintended to include a saturated mono-, bi- or poly-cyclic ring systemhaving C₃-C₁₅ carbon atom(s), preferably C₃-C₁₂ carbon atom(s); examplesof such groups include, but are not limited to, cyclopropyl, cyclobutyl,cyclohexyl, adamantyl, [3,3,0]bicyclooctantyl and [4,4,0]bicyclodecanyl;the term “cycloalkylalkyl” is intended to include connection of acycloalkyl group defined above via an alkyl group defined above;examples of such groups include, but are not limited to,2-cyclopropylethyl and 3-cyclohexyl-2-methylpropyl.

As used herein, the term “alkoxy” is alkyl-O—, wherein the alkyl groupis as defined above; examples of such groups include, but are notlimited to: methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy.

Unless stated otherwise, and irrespective of any specific substituentsbonded to alkyl groups that are indicated in the definition of thecompounds of the general formula (I), alkyl groups may be optionallysubstituted by at least one, for example 1, 2, 3, 4 or 5, identical ordifferent substituents. Any kind of substituents present in substitutedalkyl residues can be present in any desired position provided that thesubstitution does not lead to an unstable molecule. A substituted alkylrefers to an alkyl residue in which at least one, for example, 1, 2, 3,4 or 5, hydrogen atoms are replaced with substituents, for example,halogen, hydroxyl, carbonyl, such as oxo, alkoxyl, ester, ether, cyano,amino, amido, imino, sulfhydryl, alkylthio, thioester, sulfonyl, nitro,heterocyclic, aralkyl, or an aryl or heteroaryl group. The carbonbackbone of the alkyl group may be interrupted by heteroatoms such asoxygen, sulphur or nitrogen. Examples of substituted acyclic alkyls are:hydroxymethyl, hydroxyethyl, 2-hydroxyethyl, aminoethyl ormorpholinoethyl. Examples of substituted cycloalkyl groups are:cycloalkyl groups which carry as substituent at least one, for example1, 2, 3, 4 or 5, identical or different acyclic alkyl groups, forexample acyclic (C₁-C₄)-alkyl groups like methyl groups. Examples ofsubstituted cycloalkyl groups are 4-methylcyclohexyl,4-tert-butylcyclohexyl and 2,3-dimethylcyclopentyl.

It will be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate. For example, the substituents of a substituted alkyl mayinclude substituted and unsubstituted forms of amino, imino, amido,sulfonyl (including sulfonate and sulfonamide), as well as ether,alkylthio, carbonyl (including ketones, aldehydes, carboxylates, andesters), —CF₃, —CN and the like. Cycloalkyls can be further substitutedwith alkyl, alkenyl, alkoxyl, alkylthio, aminoalkyls,carbonyl-substituted alkyl, —CF₃, cyano (CN), and the like.

The term “alkenyl” as used herein can be defined as a straight orbranched hydrocarbon chain having C₂-C₁₅ carbon atoms, preferably C₂-C₁₁carbon atoms containing one or more carbon-carbon double bonds presentanywhere in the carbon chain provided that a stable compound is formed;examples of such a group include, but are not limited to: ethenyl,propenyl and pent-2-enyl.

As used herein the term “alkynyl” is defined as a straight or branchedchain hydrocarbon chain having C₂-C₁₅ carbon atoms, preferably C₂-C₁₁carbon atoms which contain one or more carbon-carbon triple bondspresent anywhere in the chain provided that a stable compound results;examples of such a group include, but are not limited to: ethynyl andpropynyl.

The terms “alkylene”, “alkenylene” and “phenylene” are intended to referto alkyl, alkenyl and phenyl groups, respectively, which are connectedby two bonds to the rest of the structure as indicated in the structureof general formula (I) or substructures or partial structures thereof,wherever applicable.

The term “aryl” as used herein refers to monocyclic or polycyclichydrocarbon groups having up to 14 ring carbon atoms in which at leastone carbocyclic ring is present that has a conjugated pi electronsystem. Examples of (C₆-C₁₄)-aryl residues are phenyl, naphthyl,biphenyl, fluorenyl and anthracenyl. The term “arylalkyl” indicates anaryl group as defined above which is attached to the indicated positionthrough an alkyl bridge.

As used herein the terms “substituted”, “substitution” or substituent”have the meaning that one or more hydrogens on the specified atom arereplaced with an atom or group selected from a defined atom or group,such that the normal valence of the atom involved is not exceeded and astable compound is provided. When a bond to a substituent is shown drawnacross the bond connecting any two given atoms in a ring, then suchsubstituent may be connected to any atom in the ring; an example of sucha group, without intending to be limiting, is R^(A) in the generalformula (I) which may be connected to any ring member; similarly when abond between an atom or group to another atom or group is notspecifically shown, such bond may be formed with any atom or group andother such atom or group. When a substituent is listed without mentionof its mode of connection i.e., the atom through which the bond isformed, then such substituent is considered to be connected via any atomin such substituent; for example a substituent shown as—O—CH═CH-includes both the substituents —O—CH═CH— and —CH═CH—O—.

The double bond ═R^(F) in general formula (I) is intended to mean both adouble bond and two single bonds at the designated point of attachment.Thus, C═R^(F) can be defined as, for example, C═O, CH(OH), CH₂, C≡N—OR¹⁹and the like.

(R^(C))s is bonded to W in general formula (I) and s can be 1, 2 or 3.Therefore, when W is —CH₂—, one or two R^(C) groups can be bonded to C,replacing one or two hydrogens, respectively, and when W is —CH₂CH₂, upto three R^(C) groups can be bonded to the two carbon atoms in W,replacing a hydrogen with each bond.

A combination of substituent(s) and/or variable(s) leading to stablecompound is permissible in the present invention. As used herein astable compound can be defined as one, which can sustain the stepsinvolved in its isolation from the reaction mixture to a useful degreeof purity and subsequent formulation into an efficacious therapeuticagent.

“Activation” refers to the change in conformation and the subsequentexposure of the otherwise inactive and unexposed GP IIb/IIIa receptors.

“Platelet aggregation” refers to the formation of clumps of platelets,which occur when fibrinogen molecules bind to the activated GP IIb/IIIareceptors and cross-link platelets.

“Thrombi” are clusters of cross-linked platelets, sometimes containingtrapped red blood cells.

“GP IIb/IIIa receptors” are glycoprotein receptors on the surface ofplatelets, which when activated recognize the Arginine-Glycine-Asparticacid (RGD) sequence in the fibrinogen molecules.

“Thrombocytopenia” is defined as a reduction in the number ofcirculating free platelets.

It is also to be understood that compounds of the present invention mayhave asymmetric centers; all enantiomers, diastereomers and racemicforms are included within the scope of the present invention. It isfurther understood that geometric isomers of olefins, C═N andconformational isomers or isomers arising out of restricted rotation, aswell understood by those familiar to the art of organic chemistry, arealso included within the scope of the present invention. Thus, racemic,R and S configurations of the compounds, as well as geometrical E/Z orsyn/anti isomers, arising from any asymmetric centre in the compoundsare included. The present invention also includes all possibleenantiomers and diastereomers in pure or substantially pure form andmixtures of two or more stereoisomers, for example mixtures ofenantiomers and/or diastereomers, in all ratios.

Prodrugs are considered to be any covalently bonded carriers thatrelease the active parent drug in vivo. In other words, a prodrug whenabsorbed in the blood stream cleaves in such a manner as to release thedrug molecule to generate desired therapeutic efficacy. Prodrugs includecompounds of general formula (I) wherein hydroxyl, amino, amidino,sulfhydryl or carboxylic groups are bonded to any group, which cleavesto form a free hydroxyl, amino, sulfhydryl or carboxyl group,respectively, on administration to a mammalian subject. Thus, thepresent invention also includes those compounds produced in vivo afteradministration of a different compound (or prodrug of the compound). Thein vivo effects of compounds described herein, may not be exerted bythose compounds as such, but by one or more degradation products.

Compounds of general formula (I) which contain one or more basic groups,i.e. groups which can be protonated, can be present and can be usedaccording to the invention in the form of their addition salts withnon-toxic inorganic or organic acids. Examples of suitable inorganicacids include: boric acid, perchloric acid, hydrochloric acid,hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitricacid and other inorganic acids known to the person skilled in the art.Examples of suitable organic acids include: acetic acid, propionic acid,succinic acid, glycolic acid, stearic acid, lactic acid, malic acid,tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid,hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid,salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid,toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid,oxalic acid, isethionic acid, ketoglutaric acid, benzenesulfonic acid,glycerophosphoric acid and other organic acids known to the personskilled in the art.

The compounds of general formula (I) which contain acidic groups can beused according to the invention, for example, as alkali metal salts likeLi, Na, and K salts, as alkaline earth metal salts like Ca, Mg salts, asaluminium salts, as salts of organic bases such as lysine, arginine,guanidine, diethanolamine, choline, tromethamine, or as salts withammonia.

The pharmaceutically acceptable salts of the present invention can besynthesized from the subject compound, which contains a basic or acidicmoiety by conventional chemical methods. Generally the salts areprepared by contacting the free base or acid with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidor base in a suitable solvent or dispersant or by anion exchange orcation exchange with other salts. Suitable solvents are, for example,ethyl acetate, ether, alcohols, acetone, THF, dioxane or mixture ofthese solvents.

The present invention furthermore includes all solvates of compounds ofgeneral formula (I), for example hydrates or adducts with alcohols.

Various polymorphs of compounds of general formula (I) forming part ofthis invention may be prepared by crystallization of compounds ofgeneral formula (I) under different conditions. For example, usingdifferent commonly used solvents or their mixtures for crystallization;crystallization at different temperatures; various modes of cooling,ranging from very fast to very slow cooling during crystallizations.Polymorphs may also be obtained by heating or melting the compoundfollowed by gradual or fast cooling. The presence of polymorphs may bedetermined by IR spectroscopy, solid probe NMR spectroscopy,differential scanning calorimetry, powder X-ray diffraction or suchother techniques.

Specifically preferred compounds of this invention are compounds thatbelong to the examples cited below, or pharmaceutically acceptable saltsor solvates thereof, selected from but not limited to:

-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid methyl ester;-   (4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid methyl ester;-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   4-(2-{5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl}-acetyl]-phenoxy)-acetic    acid isopropyl ester;-   (4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid isopropyl ester;-   (4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid isopropyl ester;-   (4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid isopropyl ester;-   (4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid isopropyl ester;-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid isobutyl ester;-   (4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid isobutyl ester;-   (4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid isobutyl ester;-   (4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid isobutyl ester;-   (4-{2-[5-(Imino-methanesulfonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid isobutyl ester;-   (4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid isobutyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;

-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid;-   (4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid benzyl ester;

(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;

-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethoxy    carbonyl methoxy-phenoxy)-acetic acid ethyl ester;-   (2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (2-Ethoxycarbonylmethoxy-4-{2-[5-(imino-{3-methyl-butyrylamino}-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-1-hydroxyimino-ethyl}-phenoxy)-acetic    acid ethyl ester;-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isobutoxy    carbonyl methoxy-phenoxy)-acetic acid isobutyl ester;-   2-(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-N,N-diethyl-acetamide;-   4-(2-{4-[2-(5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylic    acid benzyl ester;-   4-Benzyloxycarbonylamino-2-(4-{2-[5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyric    acid ethyl ester;-   4-Benzyloxycarbonylamino-2-(4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyric    acid ethyl ester;-   (4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenylsulfanyl)-acetic    acid methyl ester;-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-chloro-phenoxy)-acetic    acid ethyl ester;-   (2-Chloro-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (2-Chloro-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethyl    sulfanyl-phenoxy)-acetic acid ethyl ester;-   (2-Ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethane    sulfonyl-phenoxy)-acetic acid ethyl ester;-   (2-Ethanesulfonyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (2,6-Bis-ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (2-Acetylamino-4-{2-[5-N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(imino-isobutoxy    carbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(N-hydroxy    carbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-acetic    acid ethyl ester;-   (3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid benzyl ester;-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-acetic    acid;-   (4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-methoxy-phenoxy)-acetic    acid ethyl ester;-   (4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-propoxy-phenoxy)-acetic    acid ethyl ester;-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy    carbonylmethoxy-phenoxy)-acetic acid ethyl ester;-   (3-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid;-   (2-Ethylsulfanyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (2-Ethyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (5-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isopropyl-phenoxy)-acetic    acid ethyl ester;-   (2-tert-Butyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (2-Chloro-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (2-Chloro-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-acetic    acid ethyl ester;-   (3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-acetic    acid benzyl ester;-   (2-Ethyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-acetic    acid ethyl ester;-   (3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]acetyl}-2-propyl-phenoxy)-acetic    acid benzyl ester;-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-acetic    acid;-   (4-Hydroxy-3-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-5-methoxy-phenoxy)-acetic    acid ethyl ester;-   (3,5-Dihydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (2-Ethoxycarbonylmethoxy-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceic    acid ethyl ester;-   (2-Ethoxycarbonylmethoxy-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperazine-1-yl)-acetic    acid ethyl ester;-   (1-{2S-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-hydroxy-phenyl)-propionyl}-piperidin-4-yloxy)-acetic    acid ethyl ester;-   (1-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-acetic    acid ethyl ester;-   (1-{3-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionyl}-piperidin-4-yloxy)-acetic    acid ethyl ester;-   (1-{2-[5-(5-Methyl-isoxazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-acetic    acid ethyl ester;-   (1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-acetic    acid ethyl ester;-   (1-{2-[5-(tert-Butoxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-acetic    acid ethyl ester;-   (1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-acetic    acid;-   (4-{2-[5-Acetimidoylamino-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-acetic    acid ethyl ester;-   (3-Ethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (4-[2-(5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-3-ethoxy-phenoxy}-acetic    acid ethyl ester;-   (4-{2-[5-Carbamimdoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy-phenoxy)-acetic    acid;-   (3-Hydroxy-4-{2-[1-oxo-5-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester;-   (4-{2-[5-(Acetylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-acetic    acid ethyl ester;

(3-Acetoxy-4-{2-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;

-   (4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-acetic    acid ethyl ester;-   (3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-acetic    acid; and-   (3-Allyloxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic    acid ethyl ester.

According to a further aspect of the invention, there are providedprocesses for the preparation of the compounds of the general formula(I).

whereinring A is phenyl;R^(A) is selected from: —NO₂, —(CH₂)pCN, —C(═O)—NR¹R², —C(═S)NR¹R²,—C(═NR¹)—SMe and —C(═NR¹)—OMe, orR^(A) is selected from one of the following groups of formula (2),formula (3) and formula (4):

wherein p is 0, 1, 2, 3, 4 or 5;s is 1, 2 or 3, and when s is 2 or 3 the groups R^(A) are independent ofeach other and can be the same or different;R¹ and R² are, independently, selected from: H, hydroxy, alkyl,partially or fully fluorinated alkyl, alkoxy, alkenyl, alkynyl, carboxy,—C(═O)OR⁵, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle;or R¹ and R², together with the nitrogen atom to which they areattached, form a saturated, partially saturated, or aromaticheterocycle, optionally containing at least one additional hetero atomselected from: N, O and S;R³ and R⁴ are independently selected from: H, alkyl, partially or fullyfluorinated alkyl, alkenyl, alkynyl, —C(═O)OR⁵, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycle; —OR⁵, —SR⁵, —NR⁵R⁶,—S(═O)₂NR⁵R⁶, —S(═O)₂R⁵, —C(═O)R⁵, —C(═O)NR⁵R⁶, —C(═O)OR⁵, —C(═O)SR⁵,—OC(═O)R⁵, —OC(═O)OR⁵, —OC(═O)NR⁵R⁶, —OS(═O)₂R⁵, —S(C═O)NR⁵ and—OS(═O)₂NR⁵R⁶, orR³ and R¹ or R⁴, together with the respective nitrogen atoms to whichthey are attached, form an unsubstituted or substituted 5-, 6- or7-membered partially saturated or aromatic heterocycle, optionallyhaving one or more heteroatoms selected from: N, O and S, wherein thesubstituents are selected from: hydroxy, halogen, alkyl, alkoxy,alkenyl, alkynyl, oxo, carboxy and —C(═O)OR⁵;R⁵ and R⁶ are independently selected from: H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle, whereineach of said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkylalkylgroup optionally contains at least one hetero atom selected from: N, Sand O anywhere in the chain, including the terminal position;R⁷ and R⁹ have the same meaning as R³ and R⁴, defined above;R⁸ is selected from: H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, and heterocycle, wherein saidheterocycle is saturated, partially saturated or aromatic and containsat least one hetero atom selected from: N, O and S, with its point ofattachment either through C or N, and wherein each of said alkyl,alkenyl, alkynyl, cycloalkyl and cycloalkylalkyl groups optionallycontains at least one hetero atom selected from: N, O and S anywhere inthe chain, including the terminal position;R^(B) is selected from: H, halogen, —CN, —NO₂, alkyl, partially or fullyfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycle, —NR¹⁰R¹¹, —OR¹⁰, —SR¹⁰, S(O)R¹⁰, S(O)₂R¹⁰,—NHC(═O)R¹⁰, —NHOR¹⁰, —OC(═O)R¹⁰, —SC(═O)R¹⁰, —NHC(═O)OR¹⁰, —OC(═O)OR¹⁰,—C(═O)NR¹⁰R¹¹, —C(═O)R¹⁰, and —C(═O)OR¹⁰;R¹⁰ and R¹¹ have the same meaning as R⁵ or R⁶, defined above;s is 1, 2 or 3 and when s is 2 or 3 the groups R^(B) are independent ofeach other and can be same or different;Y¹ and Y² are independently selected from: H, R¹², R¹³, NR¹²R¹³, OR¹²,SR¹², CH₂(OR¹²), CH₂(SR¹²), CH₂S(═O)R¹² and CH₂S(═O)₂R¹², orY¹ and Y², together, are selected from: ═O, ═S, ═CR¹²R¹³, ═NR¹² and═N—OR¹²;R¹² and R¹³ are selected from: H, OR⁵, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl and aryl;

Z is CH or N;

W is (CH₂)_(u), wherein u is the integer 1 or 2;R^(C) is selected from: R⁵, ═O, ═NR¹⁴, ═S, CN, NR¹⁴R¹⁵, OR¹⁴, SR¹⁴,S(═O)₂R¹⁶ and COR¹⁶;R¹⁴ and R¹⁵ have the same meaning as R⁵ and R⁶, defined above;s is 1, 2 or 3 and when s is 2 or 3 the groups R^(C) are independent ofeach other and can be same or different;R¹⁶ is selected from: H, OR¹⁴, N(R¹⁴)₂, NR¹⁴R¹⁵, SR¹⁴ and R⁵, whereinR⁵, R¹⁴ and R¹⁵ are as defined above;n is 0, 1, 2, 3, 4 or 5;R^(D) and R^(E) are independently selected from: H and an unsubstitutedor substituted group selected from: alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl and heterocycle, wherein thesubstituents are selected from: hydroxy, halogen, alkyl, alkenyl,alkynyl, oxo, carboxy, —C(═O)OR⁵, —OR¹⁷, —SR¹⁷, —NR¹⁷R¹⁸, —NHC(═O)R¹⁷,—NHC(═O)OR¹⁷, —OC(═O)R¹⁷, —SC(═O)R¹⁷, —OS(═O)₂R¹⁷ and —NHS(═O)₂R¹⁷;R¹⁷ and R¹⁸ have the same meaning as R⁵ and R⁶, defined above;R^(F) is selected from: (H, H), (—H, —OH), O, S, N(OR¹⁹), N[OC(═O)OR¹⁹],N[OC(═O)R¹⁹] and N[OS(═O)₂NR¹⁹R²⁰], wherein R¹⁹ and R²⁰ have the samemeaning as R⁵ and R⁶, defined above;R^(G) is selected from: aryl, heteroaryl, and partially or fullysaturated heterocycle, wherein said aryl, heteroaryl, and heterocycleare substituted by one or more groups independently selected from: —R⁵,halogen, —CN, —SCN, —CNO, —OR²¹, —OC(═O)R²¹, —OS(═O)₂R²¹,—OS(═O)₂NR²¹R²², —OC(═O)OR²¹, —OC(═O)SR²¹, —OC(═O)NR²¹R²², —SR²¹,—S(═O)R²¹, —SC(═O)H, —SC(═O)OR²¹, —NO₂, —NR²¹(OR²²), —NR²¹R²²,—NR²¹C(═O)R²², —N(R²¹)C(═O)OR²², —N[S(═O)₂R²¹]R²³, C(═O)OR²¹,—S(═O)₂R²¹, —S(═O)₂OR²¹ and a group of formula (5):

T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5)

R²¹ and R²² have the same meaning as R¹ and R², defined above;T is selected from: —CH₂, O, S and NH;q is 0, 1, 2, 3, 4, 5 or 6;R²³ and R²⁴ are independently selected from: H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, and C(═O)R²⁵,wherein said alkyl and alkenyl optionally contain at least one heteroatom selected from: O, S and N, in any position of the alkyl or alkenylchain, and said alkyl and alkenyl are unsubstituted or substituted withat least one group selected from: —OR¹, —OS(═O)₂R¹, —S(═O)₂NR¹R²,—OC(═O)OR¹, —OC(═O)SR¹, —OC(═O)NR¹R², —SR¹, —S(═O)R¹, —SC(═O)H,—SC(═O)OR¹, —NR¹ (OR²), —NR¹R², —NR¹C(═O)R², —N(R¹)C(═O)OR²,—NR¹S(═O)₂R², C(═O)OR¹, —S(═O)₂R¹ and —S(═O)₂OR¹;R²⁵ is selected from: OR⁵, SR⁵, —OCR³R⁴ and —NR⁵R⁶, wherein R³, R⁴, R⁵and R⁶ are as defined above and wherein, optionally, R³ and R⁴, togetherwith the carbon atom to which they are attached, form an unsubstitutedor substituted 5-, 6- or 7-membered saturated, partially saturated oraromatic heterocycle, having one or more heteroatoms selected from: N, Oand S, wherein the substituents are selected from: hydroxy, halogen,alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy and —C(═O)OR⁵; and thegroup NR⁵R⁶ is, optionally, a heterocycle containing at least oneadditional heteroatom selected from: O, S, and N;which process comprisesreacting compound of formula (II):

whereinL is a leaving group, such as halogen, for example Br; and all othersymbols are as defined above; witha compound of the formula (III):

wherein all symbols are as defined above; in the presence of an organicbase such as dimethylaminopyridine, purine base, pyridine,triethylamine, or inorganic base such as sodium bicarbonate, sodiumcarbonate, lithium carbonate, lithium hydroxide, potassium bicarbonate,potassium carbonate, in an organic solvent such as dichloromethane,chloroform, N,N-dimethylformamide, tetrahydrofuran, dioxan, methanol,ethanol, isopropanol or a mixture of at least two different organicsolvents, at a temperature ranging from −40° C. to 150° C., for 0.5 to16 h, to effect in situ cyclization to form a compound of the generalformula (I) above, and, optionally, converting the compound into aphysiologically tolerable salt or prodrug.

Another aspect of the present invention provides an alternative processfor the preparation of a compound of the general formula (I),

which process comprises reacting a compound of the formula (IV)

whereinL₂ is a leaving group such as halogen, preferably chlorine; and allother symbols are as defined above;with a compound of the formula (V):

where R^(G) is selected from: piperidinyl, piperazinyl and phenyl,wherein said piperidinyl, piperazinyl and phenyl, are optionallysubstituted with 1, 2, 3 or 4 hydroxyl groups, for example 2 hydroxylgroups, and all other symbols are as defined above, in the presence ofan organic base such as dimethylaminopyridine, purine base, pyridine,triethylamine, or inorganic base such as sodium bicarbonate, sodiumcarbonate, lithium carbonate, lithium hydroxide, potassium bicarbonate,potassium carbonate in an organic solvent such as dichloromethane,chloroform, N,N-dimethylformamide, tetrahydrofuran, dioxan, methanol,ethanol, isopropanol, ethyl acetate or water at a temperature rangingfrom 0° C. to 150° C., for 0.5 to 12 h, to form a compound of thegeneral formula (I), and,optionally, converting one or more of the hydroxyl groups into adifferent group selected from the substituents for R^(G) as defined ingeneral formula (I) and, optionally, converting the resultant compoundof general formula (I) into a physiologically tolerable salt or prodrug;alternatively,activating a compound of the formula (IV) above, wherein L₂ is —OH, bytreatment with a mixed anhydride to form a peptide coupling with acompound of the formula (V), wherein R^(G) is piperidinyl orpiperazinyl, and thereby provide a compound of the general formula (I),wherein R^(G) is piperidinyl or piperazinyl, substituted with at least agroup of the formula 5; and, optionally, converting the resultantcompound of general formula (I) into a physiologically tolerable salt orprodrug.

Yet another aspect of the present invention provides a process for thepreparation of a compound of the general formula (I), wherein R^(G) isphenyl substituted with a group of the formula (5) or —OCH₂Phenyl, and,optionally, substituted with at least one further group selected from:—R⁵, halogen, —CN, —SCN, —CNO, —OR²¹, —OC(═O)R²¹, —OS(═O)₂NR²¹R²²,—OC(═O)OR²¹, —OC(O)SR²¹, —OC(═O)NR²¹R²², —SR²¹, —S(═O)R²¹, —SC(═O)H,—SC(═O)OR²¹, —NO₂, —NR²¹(OR²²), NR²¹R²², —NR²¹C(═O)R²²,—N(R²¹)C(═O)OR²², —N[S(═O)₂R²¹]R²³, C(═O)OR²¹, —S(═O)₂R²¹, —S(═O)₂OR²¹and a group of the formula 5;

W is —(CH₂)_(u) wherein u is 2; and all other symbols are as definedabove;which process comprises alkylating a compound of the formula (VI):

wherein all symbols are as defined above;with a compound of the formula (VII)

whereinL₃ is a leaving group; and all other symbols are as defined above;in the presence of an organic base such as dimethylaminopyridine, purinebase, pyridine, triethylamine, or inorganic base such as sodiumbicarbonate, sodium carbonate, lithium carbonate, lithium hydroxide,potassium bicarbonate, potassium carbonate, in an organic solvent suchas dichloromethane, chloroform N,N-dimethylformamide, tetrahydrofuran,dioxan, methanol, ethanol, isopropanol, or a mixture of at least twodifferent organic solvents, at a temperature ranging from −40° C. to150° C., for 0.5 to 16 h, to effect in situ cyclization to form acompound of the general formula (I) as defined above,and when R^(G) is substituted with —OCH₂Phenyl, optionally convertingthe —OCH₂Phenyl into hydroxyl and subsequently coupling the hydroxylwith the group L₄-(CH₂)_(q)—CR²³R²⁴—COR²⁵, wherein L₄ is a leavinggroup, such as halogen, OMes or OTs; and all the other symbols are asdefined in general formula (I);optionally converting the —(CH₂)pCN group into a group of the formula 3;and,optionally, converting the resultant compound into a physiologicallytolerable salt or prodrug.

Yet another aspect of the present invention provides a process for thepreparation of a compound of the general formula (I), wherein R^(G) isphenyl, having at least one substituent which is OCH₂Phenyl, andoptionally at least one further substituent selected from: —R⁵, halogen,—CN, —SCN, —CNO, —OR²¹, —OC(═O)R²¹, —OS(═O)₂R²¹, —OS(═O)₂NR²¹R²²,—OC(═O)OR²¹, —OC(═O)SR²¹, —OC(═O)NR²¹R²², —SR²¹, —S(═O)R²¹, —SC(═O)H,—SC(═O)OR²¹, —NO₂, —NR²¹OH, —NR²¹(OR²²), —NR²¹R²², NR²¹C(═O)R²²,—N(R²¹)C(═O)OR²², —N[S(═O)₂R²¹]R²³, C(═O)OR²¹, —S(═O)₂R²¹ and—S(═O)₂OR²¹; and

W is —(CH₂)_(u) where u is 1;which process comprises, alkylating a compound of the formula (VIII)

wherein B is halogen, acetate, formate; and all other symbols are asdefined above;with a compound of the formula (VII):

whereinL₃ is a leaving group, such as halogen, tosyl, mesyl; and all othersymbols are as defined above;in the presence of an organic base such as dimethylaminopyridine, purinebase, pyridine, triethylamine, or inorganic base such as sodiumbicarbonate, sodium carbonate, lithium carbonate, lithium hydroxide,potassium bicarbonate, potassium carbonate, in an organic solvent suchas dichloromethane, chloroform, N,N-dimethylformamide, tetrahydrofuran,dioxan, methanol, ethanol, isopropanol, or a mixture of at least twodifferent organic solvents, at a temperature ranging from −40° C. to150° C., for 0.5 to 16 h, to effect in situ cyclization to form thecompound of general formula (I), wherein R^(A) is —COOEt and s is 2;optionally converting one or both of the —COOEt groups into the cyanogroup —(CH₂)pCN, wherein p is as defined; optionally, subsequentlyconverting at least one of the cyano groups into a compound of theformula 3, as defined; and,optionally, converting the resultant compound into a physiologicallytolerable salt or prodrug.

The present invention further relates to novel process for thepreparation of intermediates H63, G48, G54 and H69 identified below,required for the synthesis of the compounds of general formula (I).

Accordingly, there is provided a process for the preparation ofintermediate H-63:

wherein R is a group of formula (5), below:

T(CH₂)_(q)CR²³R²⁴COR²⁵  (5)

whereinT is selected from: —CH₂, O, S and NH;q is 0, 1, 2, 3, 4, 5 or 6;R²³ and R²⁴ are independently selected from: H, alkyl and alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle andC(═O)R²⁵, wherein said alkyl and alkenyl optionally contain at least onehetero atom selected from: O, S and N, in any position of the alkyl oralkenyl chain, and said alkyl and alkenyl are unsubstituted orsubstituted with at least one group selected from: —OR¹, —OC(═O)R¹,—OS(═O)₂R¹, —S(═O)₂NR¹R², —OC(═O)OR¹, OC(═O)SR¹, —OC(═O)NR¹R², —SR¹,—S(═O)R¹, —SC(═O)H, —SC(═O)OR¹, —NR¹(OR²), —NR¹R², —NR¹C(═O)R²,—N(R¹)C(═O)OR², —NR¹S(═O)₂R², C(═O)OR¹, —S(═O)₂R¹ and —S(═O)₂OR¹;R¹ and R² are as defined in general formula (I) above;R²⁵ is selected from: OR⁵, SR⁵, —OCR³R⁴ and —NR⁵R⁶, wherein R³, R⁴R⁵ andR⁶ are as defined in general formula (I), and wherein, optionally, R³and R⁴, together with the carbon atom to which they are attached, forman unsubstituted or substituted 5-, 6- or 7-membered saturated,partially saturated or aromatic heterocycle having one or moreheteroatoms selected from: N, O and S, wherein the substituents areselected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo,carboxy and —C(═O)OR⁵; and the group NR⁵R⁶ is, optionally, a heterocyclecontaining at least one additional heteroatom selected from: O, S, andN;R′ is H, a protected amino group, such as NHZ, or L, wherein L is aleaving group, such as halogen, OMes or OTs;R^(D) and R^(E) are independently selected from: H and an unsubstitutedor substituted group selected from: alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl and heterocycle, wherein thesubstituents are selected from: hydroxy, halogen, alkyl, alkenyl,alkynyl, oxo, carboxy, —C(═O)OR⁵, —OR¹⁷, —SR¹⁷, —NR¹⁷R¹⁸, —NHC(═O)R¹⁷,—NHC(═O)OR¹⁷, —OC(═O)R¹⁷, —SC(═O)R¹⁷, —OS(═O)₂R¹⁷ and —NHS(═O)₂R¹⁷;R¹⁷ and R¹⁸ have the same meaning as R⁵ and R⁶;

R^(F) is ═O; and

n is 0, 1, 2, 3, 4 or 5;which process comprises reacting the O-allylic compound H-60

wherein R^(a), R^(b) and R^(c) are independently selected from: alkyland alkylaryl, and R has the meaning defined above, with the compoundR′(CH₂)_(n)CR^(D)R^(E)COCl, wherein R′, R^(D), R^(E) and n are asdefined above, in the presence of a Lewis acid catalyst such as Zn,BF₃.etherate, FeCl₃, AlCl₃ and ZnCl₂, preferably Zn, in the presence ofan organic solvent or mixture of at least two organic solvents selectedfrom, for example: toluene, benzene, heptane, kerosene, CS₂, CCl₄ andnitrobenzene, preferably toluene, at a temperature ranging from roomtemperature to 120° C., for a period of 2 to 12 h and, optionally,isolating the intermediate H-63 from the reaction mixture. This is asingle step process in which the O-allylic compound H60 may undergocleavage during the reaction.

There is also provided a novel process for the preparation of novelintermediates G48, G54 and H69 required for the synthesis of a compoundof the general formula (I):

whereinR^(K), R^(L), R^(V) and R^(U), are independently selected from: H,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,halogen, —CN, —SCN, —CNO, —OR²¹, —OC(═O)R²¹, —OS(═O)₂R²¹,—OS(═O)₂NR²¹R²², —OC(═O)OR²¹, —OC(═O)SR²¹, —OC(═O)NR²¹R²², —SR²¹,—S(═O)R²¹, —SC(═O)H, —SC(═O)OR²¹, —NO₂, —NR²¹(OR²²), —NR²¹R²²,—NR²¹C(O)OR²², —N(R²¹)C(═O)OR²², —N[S(═O)₂R²¹]R²³, C(═O)OR²¹,—S(═O)₂R²¹, —S(═O)₂OR²¹ and a group of formula (5):

T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5)

whereinT is selected from: —CH₂, O, S and NH;q is 0, 1, 2, 3, 4, 5 or 6;R²³ and R²⁴ are independently selected from: H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle and C(═O)R²⁵,wherein said alkyl and alkenyl optionally contain at least one heteroatom selected from: O, S and N, in any position of the alkyl or alkenylchain, and said alkyl or alkenyl are unsubstituted or substituted withat least one

group selected from: —OR¹, —OC(═O)R¹, —OS(═O)₂R¹, —S(═O)₂NR¹R²,—OC(═O)OR¹, —OC(═O)SR¹, —OC(═O)NR¹R², —SR¹, —S(═O)R¹, —SC(═O)H,—SC(═O)OR¹, —NR¹(OR²), —NR¹R², —NR¹C(═O)R², —N(R¹)C(═O)OR²,—NR¹S(═O)₂R², C(═O)OR¹, —S(═O)₂R¹ and —S(═O)₂OR¹;

wherein R¹, R², R²¹ and R²² are as defined in general formula (I);R²⁵ is selected from: OR⁵, SR⁵, —OCR³R⁴ and —NR⁵R⁶, wherein R³, R⁴, R⁵and R⁶ are as defined in general formula (I), and wherein, optionally,R³ and R⁴, together with the carbon atom to which they are attached,form an unsubstituted or substituted 5-, 6- or 7-membered saturated,partially saturated or aromatic heterocycle having one or moreheteroatoms selected from: N, O and S, wherein the substituents areselected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo,carboxy and —C(═O)OR⁵; and the group NR⁵R⁶ is, optionally, a heterocyclecontaining at least one additional heteroatom selected from: O, S, andN; with the proviso that at least one of the groups R^(K), R^(L), R^(V)and R^(U) is OH;R^(D) and R^(E) are independently selected from: H and an unsubstitutedor substituted group selected from: alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl and heterocycle, wherein thesubstituents are selected from: hydroxy, halogen, alkyl, alkenyl,alkynyl, oxo, carboxy, —C(═O)OR⁵, —OR¹⁷, —SR¹⁷, —NR¹⁷R¹⁸, —NHC(═O)R¹⁷,—NHC(═O)OR¹⁷, —OC(═O)R¹⁷, —SC(═O)R¹⁷, —OS(═O)₂R¹⁷ and —NHS(═O)₂R¹⁷;R¹⁷ and R¹⁸ have the same meaning as R⁵ and R⁶;R′ is H, a protected amino group, such as NHZ, NHTroc or NHFmoc,preferably NHZ, or a leaving group; andn is 0, 1, 2, 3, 4 or 5;which process comprises reacting a mono- or polyhydroxy phenol of theformula (IX):

whereinR²¹ is selected from H, alkyl or aralkyl; andR^(K), R^(L), R^(V) and R^(U) have the meaning defined above, preferablyR^(K) and/or R^(U)═—OHwith a compound of the formula X:

R′(CH₂)_(n)CR^(D)R^(E)CN  (X),

in which R^(D) and R^(E) & n have the meaning defined hereinabove;in the presence of an inorganic acid, such as HCl or HBr, and a Lewisacid catalyst, such as Zn, BF₃.etherate, FeCl₃, AlCl₃ or ZnCl₂,preferably ZnCl₂, and, optionally, isolating the resultant intermediatefrom the reaction mixture.

The reaction may be carried out at 0° C. to 60° C., preferably at 0° C.to ambient temperature, for a period of 2 to 12 h. in at least onesolvent selected from, for example: ether, benzene, THF and dioxane,preferably ether.

Examples of the polyhydroxy phenol that may be used in the process ofthe present invention are the intermediates G-47, H-65 and H-68, givenbelow:

wherein R²¹ is as defined in respect of general formula (I). Specificexamples of the polyhydroxy phenol include: 2 or 4 substitutedresorcinol; 1,2,3 trihydroxyphenol; 1,2,4 trihydroxyphenol; and 1,3,5trihydroxyphenol.

Synthesis

The compounds of the present invention can be synthesized by the methodsdescribed below, with reference to the schemes in Figures A-H, J and K.Some steps in the methods may include synthetic methods known in the artof synthetic organic chemistry or a modification thereof, as appreciatedby those skilled in the art. However, the methods of preparation of thecompounds of the present invention are not limited to those methodsdescribed below. The reactants and intermediates used in the processesdescribed are either commercially available or can be prepared accordingto standard literature procedures.

All references cited here are hereby incorporated in their entiretyherein by reference.

The following abbreviations are used herein:

-   -   AcOH: acetic acid    -   Ac₂O: acetic anhydride    -   AIBN: 2,2′-azobis-(2-methylpropionitrile)        -   /2,2′-azobisisobutyronitrile    -   β-Ala: 3-aminopropionic acid    -   Boc: tert-butyloxycarbonyl    -   Boc₂O: di-tert-butyl dicarbonate    -   DCC: 1,3-dicyclohexylcarbodiimide    -   DCU: 1,3-dicyclohexyl urea    -   DEA: diethyl amine    -   DIEA diisopropylethyl amine    -   DMAP: 4-dimethylaminopyridine    -   DMF: N,N-dimethylformamide    -   DMSO: dimethylsulfoxide    -   EtOAc: ethyl acetate    -   EtOH: ethyl alcohol    -   Fmoc: Fluorenyl methyloxy carbonyl    -   HOBt: 1-hydroxybenzotriazole    -   IBCF: iso-butylchloroformate    -   IPA: iso-propyl alcohol    -   MCPBA: meta-chloroperbenzoic acid    -   MeOH: methanol    -   NBS: N-bromosuccinimide    -   NCS: N-chlorosuccinimide    -   NIS: N-iodosuccinimide    -   NMM: N-methylmorpholine    -   NMP: N-methylpyrrolidine    -   PPh₃: triphenylphosphine    -   PTSA: 4-toluenesulfonic acid    -   Pyr: pyridine    -   TEA: triethylamine    -   TFA: trifluoroacetic acid    -   THF: tetrahydrofuran    -   Troc 2,2,2-trichloroethoxycarbonyl    -   Tyr: L-tyrosine    -   Z: benzyloxycarbonyl

The symbols used herein R¹ to R²⁵, R^(A), R^(B), R^(C), R^(D), R^(E),R^(F), R^(G), n, q, Z, W and T have the same meaning as described forthe general formula (I), unless otherwise indicated; L is a leavinggroup such as halogen, OMes or OTs; Q is CH or N. For the purpose ofdescribing the synthesis, Y¹ and Y² together, are ═O; R isT(CH₂)_(q)CR²³R²⁴COR²⁵; and R′ is H, a leaving group (L) or a protectedamine, such as —NHZ.

A convenient method for the synthesis of compounds of the presentinvention involves alkylation of an appropriately substituted aminocompound with a suitable alkylating agent and in situ cyclizationfollowed by reaction steps involving functional group modification.Examples of similar cyclization steps have been described in U.S. Pat.No. 5,719,144.

Compounds of general formula (I) above may be derived from keyintermediates designated as A-8/B-20 and B-19. The preparation of theseintermediates by alternative reaction sequences is depicted in theschemes shown in Figures A (compound A-8) and B (compounds B-19 andB-20), which are provided in the accompanying drawings.

Figure A

The preparation of variants of the key intermediate A-8 by alternativereaction sequences are described in the following processes designatedherein as processes 1-1, 1-2, 1-3 and 1-4, which are schematicallypresented in Figure A.

Process 1-1 for the Preparation of Compound A-8 (R^(A) is NO₂, R^(B) andR^(C) are H)

-   -   (i) An appropriately substituted o-tolylamine may be subjected        to a Sandmeyer reaction (Vogel's Textbook of Practical Org.        Chem., 5^(th) edition, 938) to obtain the corresponding cyano        compound, which may be hydrolysed with 50-75% aqueous H₂SO₄ at        100°-150° C. for 12-24 hrs in accordance with a known procedure        (Vogel's Textbook of Practical Org. Chem., 5^(th) edition,        1063). The resulting acid may further be converted to its        corresponding ester designated as A-1 by any standard procedure        known in the art. Alternatively, ester A-1 may also be obtained        from the cyano compound by alcoholysis in presence of a mineral        acid under reflux.    -   (ii) The methyl group in A-1 may be converted to CH₂L (wherein L        represents a leaving group, e.g. Br), by any conventional method        known in the art. One suitable method for said conversion        involves treating the ester A-1 with NBS in presence of AIBN or        dibenzoyl peroxide under reflux in an organic solvent, such as        carbon tetrachloride, chloroform or carbon disulphide, for 2-24        h to obtain the compound designated as A-2.    -   (iii) The resulting compound A-2 may then be converted to the        desired compound A-8 (R^(A) is NO₂, R^(B) and R^(C) are H, W is        CH₂) by alkylation followed by in situ cyclization with        compounds designated herein as H-72, J-77 and K-84. Said        cyclization step may be carried out in presence of an organic        base, such as TEA, DMA or pyridine, or an inorganic base, such        as NaHCO₃, Na₂CO₃, KHCO₃, K₂CO₃, Cs₂CO₃, or CsOH, in an organic        solvent, such as CH₂Cl₂, CHCl₃, MeOH, EtOH, iPrOH, THF, dioxane        or DMF, or a mixture of at least two of said solvents, at a        temperature ranging from −40° C. to reflux; preferably at        −25° C. to ambient temperature.

The synthesis of the compounds H-72, J-77 and K-84 are describedhereinafter in processes 8-2, 9-1 and 10-1, respectively.

Process 1-2 for the Preparation of Compound A-8 (R^(A) is CN, R^(B) andR^(C) are H):

-   -   (i) The nitro group in the ester A-1 may be reduced to the        corresponding amine designated as A-3 by catalytic hydrogenation        or transfer hydrogenation with ammonium formate in presence of a        catalyst, such as Pd, Pt, Pd—C or Pt—C, or with Raney Ni, in an        organic solvent such as EtOAc, MeOH, EtOH, iPrOH, DMF, or a        combination of at least two of said solvents. This reduction may        also be carried out by various conventional methods known in the        art for converting a nitro group to an amino group. One suitable        method uses Zn and CoCl₂.6H₂O as described in a reported        procedure (Ind. J. Chem., 1994, 33B 758).    -   (ii) The amino group in compound A-3 may then be converted to a        cyano group by a Sandmeyer reaction (Vogel's Textbook of        Practical Org. Chem., 5^(th) edition, 938). The resulting        compound may be subsequently converted to compound A-4 in a        manner similar to that described hereinabove for the conversion        of compound A-1 to compound A-2.    -   (iii) The compounds H-72, J-77 and K-84 may be subjected to        alkylation and in situ cyclization with compound A-4 by a        procedure as described hereinabove for the conversion of        compound A-2 to the desired compound A-8 (R^(A) is CN).        Process 1-3 for the Preparation of Variants of Compound A-8        (R^(A) is CN; R^(B) is COR¹⁰, OR¹⁰, C₁-C₁₅-alkyl, hologen, SR¹⁰,        S(O)R¹⁰, S(O)₂R¹⁰, NHCOR¹⁰, NHCOOR¹⁰, NO₂, or NHZ/NHTroc; and        R^(C) is H):

(i) Preparation of Variants of Compound A-5:

-   -   a) The compound A-5 (R^(B) is COR¹⁰) may be prepared by first        protecting the amino group in compound A-3 with an appropriate        protecting group (eg. phthaloyl) and then subjecting the        resulting compound to Friedel-Crafts acylation with a suitable        acylating agent, such as an acid chloride or an anhydride,        followed by deprotection of the amino group by any conventional        method known in the art.    -   b) The compound A-5 (R^(B) is C₁-C₁₅-alkyl) may be prepared by        first protecting the amino group in compound A-3 with an        appropriate protecting group (eg. phthaloyl) and then subjecting        the resulting compound to Friedel-Crafts alkylation followed by        deprotection of the amino group. Alternatively, said compound        A-5 may be prepared by reducing the carbonyl group in the        compound of the type A-5 (wherein R^(B) is CO C₁-C₁₄-alkyl),        which after reduction results in CH₂C₁-C₁₄-alkyl, according to a        reported procedure (Synthesis, 763, 1978; Tetrahedron, 23, 2235,        1967).    -   c) The compound A-5 (R^(B) is halogen, such as Cl, Br, I) may be        prepared by treating compound A-3 with N-halosuccinimide in an        organic solvent, such as DMF, acetonitrile, AcOH, CHCl₃, CS₂,        CH₂Cl₂ or a mixture of at least two of said solvents, at a        temperature ranging from 0°-100° C.    -   d) The compound A-5 (R^(B) is OR¹⁰) may be prepared by first        protecting the amino group in the compound A-5 (R^(B) is Cl, Br        or I) with a suitable protecting group, such as Boc or Z, and        subsequently treating the resulting compound with an alkali        metal alkoxide in the presence of CuCl, CuBr or CuI in        accordance with a reported procedure (Tetrahedron, 48, 3633,        1992; J. Org. Chem., 62, 5413, 1997), followed by deprotection        of the amino group.    -   e) Compound A-5 (R^(B) is SR¹) may be prepared by treating the        compound A-5 (R^(B) is Cl, Br or I) with CuSR¹⁰ in accordance        with a reported procedure (J. Am. Chem. Soc, 81, 4927, 1959).        The resulting compound A-5 (R^(B) is SR¹⁰) may be converted to        its corresponding sulfoxide or sulfone [R^(B) is S(O)R¹⁰ or        S(O)₂R¹⁰] by subjecting it to oxidation.    -   f) Compound A-5 (R^(B) is NO₂) may be prepared by first        protecting the amino group in compound A-3 with a suitable        protecting group (e.g. phthaloyl) and subjecting the resulting        compound to a standard nitration reaction followed by        deprotection of the amino group by any conventional method known        in the art.    -   Alternatively, prior to deprotection, the nitro group in the        resulting compound may be reduced to the corresponding amino        group by following the same procedure as described hereinabove        for the conversion of compound A-1 to compound A-3. The newly        formed amino group may be protected with a different protecting        group, such as Z or Troc, so that it is compatible with the        phthaloyl group and does not interfere at the time of deblocking        the phthaloyl protecting group. The phthaloyl group may then be        removed to obtain the corresponding compound A-5 (R^(B) is NHZ        or NHTroc).    -   Alternatively, the amino compound prior to deprotection of        phthaloyl group may be treated with an appropriate acid chloride        or a choloroformate using a standard procedure in the art to        obtain the desired compound A-5 (R^(B) is NHCOR¹⁰ or NHCOOR¹⁰).        (ii) The thus obtained variants of compound A-5 may be converted        to the corresponding compound A-6 by a procedure as described        hereinabove for the conversion of compound A-3 to compound A-4.        (iii) The compounds H-72, J-77 and K-84 may be subjected to        alkylation and in situ cyclization with compound A-6 by a        procedure as described above in process 1-1, to obtain the        desired compound A-8 (R^(A) is CN, R^(B) is as defined above and        R^(C) is absent).        (iv) Alternatively, the compound A-8 may also be obtained from        compound A-7, which in turn can be obtained from compound A-6.        The —CH₂Br group in compound A-6 may be converted to —CH₂CN or        —CH₂CH₂NO₂ by using any conventional method. One such method for        converting the —CH₂Br group to —CH₂CN is by treating the halide        with an alkali metal cyanide or Zn(CN)₂ in a suitable solvent,        such as DMF, DMSO or alcohol. One method for converting the        —CH₂Br group to —CH₂CH₂NO₂ is by treating the halide with nitro        methane in the presence of a suitable base, such as NaOEt or        NaH. The nitrile or nitro group is then reduced to an amino        group by any conventional method known in the art. One such        method involves catalytic hydrogenation as described hereinabove        to obtain the compound A-7.    -   The resulting compound A-7 may then be converted to the desired        variants of compound A-8, wherein W is CH₂CH₂ (R^(C) is H) and        other symbols are as defined earlier, by alkylation followed by        in situ cyclization with compounds designated herein as F-46,        G-53, H-63, wherein R′ is a leaving group, such as Cl, Br, I,        OMes and OTs, and J-74. The synthesis of the compounds F-46,        G-53, H-63 and J-74 are described hereinafter in processes 6-1,        7-1, 8-1 and 9-1, respectively.

Process 1-4 for the Preparation of Other Variants of Compound A-8:

-   -   (i) The intermediates A-2, A-4 and A-6 may alkylate amines of        the type H₂N(CH₂)₂CR^(D)R^(E)COOR¹ (wherein R¹ is Me/Et/CH₂Ph)        followed by cyclization to obtain a compound designated as A-9.        Likewise, the intermediate A-7 may undergo alkylation with        L₃(CH₂)_(n)CR^(D)R^(E)COOR¹ to obtain the compound A-9.    -   (ii) The compound A-9 may be hydrolysed with aqueous LiOH in an        organic solvent, such as MeOH, EtOH, iPrOH, THF, dioxane and        DMF, to obtain the corresponding acid A-10. The protecting group        (R¹) of the ester, such as the benzyl group, may also be removed        by catalytic hydrogenolysis of A-9 to obtain the corresponding        acid A-10.    -   (iii) The acid thus obtained may then be coupled with compounds        designated as K-81 or K-83 via a standard peptide coupling        procedure, preferably with DCC, by a mixed anhydride method or        by using any other method for activation of the acid to give        further variants of compound A-8.    -   (iv) Alternatively, the acid A-10 may further be converted to        its acid chloride A-11 by any conventional method, for example,        by treating said acid with SOCl₂. The thus obtained acid        chloride may be coupled with compounds designated as K-81 or        K-83 in the presence of organic bases, such as TEA, pyridine or        DIPEA and inorganic bases such as NaOH, Na₂CO₃, or CsCO₃. The        synthesis of the compounds K-81 and K-83 are described        hereinafter in process 10-1.    -   (v) Alternatively, a suitably substituted mono or polyhydroxy        phenol derivative, such as H65, H68 and G47, may be subjected to        a Friedel-Crafts acylation with the acid chloride A-11 using a        Lewis acid catalyst or by using activated Zn as reported in the        literature (Synth. Commun, 28, 2203, 1998), to obtain yet        another variant of compound A-8.

Figure B

The preparation of variants of the key intermediate B-19 and B-20 byalternative reaction sequences is described below by the processesdesignated as processes 2-1, 2-2, 2-3 and 2-4, which are schematicallypresented in Figure B:

Process 2-1 for the Preparation of Compounds B-20 (R^(B) is H):

-   -   (i) 4-Methylbenzoic acid may be treated with bromine in presence        of AgNO₃ according to a reported method (J. Org. Chem., 25,        1024, 1960) to obtain 3-bromo-4-methylbenzoic acid. The methyl        group in the resulting compound may be oxidized by any        conventional oxidizing agent, for example, alkaline potassium        permanganate at a temperature ranging from 50°-100° C. for 2-6        hr to obtain the corresponding dicarboxylic acid. The resulting        dicarboxylic acid (Beil, 9, IV, 3335) may be esterified by        refluxing with an appropriate alcohol (e.g. EtOH) in presence of        a mineral acid or by treatment with SOCl₂ followed by addition        of an appropriate alcohol (e.g. EtOH) to give a compound        designated as B-12.    -   (ii) The bromo compound B-12 may then be converted to a cyano        compound by treating it with a reagent, such as CuCN, alkali        metal cyanide or Zn(CN)₂, in a solvent, such as pyridine, DMF, a        lower alcohol, or pyrrolidone; at a temperature ranging from        50°-150° C. for 3-24 hr. The resulting cyano compound may then        be subjected to catalytic hydrogenation in a solvent, such as an        alcohol, AcOH, chloroform, DMF, or a mixture of at least two of        said solvents, at 200-500 psi, preferably in an alcohol and        chloroform mixture over PtO₂ at 400 psi for 2-8 hr to obtain a        compound designated as B-13, wherein B is, for example, halogen,        acetate or formate.    -   (iii) The compound B-13 may then be subjected to alkylation with        R^(G)(C═R^(F))CR^(D)R^(E)(CH₂)_(n)L₃ and in situ cyclization to        obtain a compound designated as B-16, wherein the groups R^(K),        R^(L), R^(U) and R^(V) are the same as the ring substituents in        the definition of R^(G). In compound B-16, R^(G) is not        substituted with a —COOR group. The ester group (R^(A)═—COOEt)        in compound B-16 may be converted to a cyano group by any        conventional method, for example, through amide formation        followed by dehydration by a number of reagents well known in        the art, to obtain a compound designated as B-17, wherein        R^(A)═—CN.    -   Alternatively, the ester group (R^(A)) in the compound B-16 may        be converted to a —(CH₂)_(p)CN group by a number of synthetic        steps. These steps involve hydrolysis of an ester to an acid,        reduction of the resulting acid to an alcohol by any        conventional reducing agent, such as NaBH₄— mixed anhydride        (except in cases in which R^(F) is O and S). The resulting        alcohol is converted to a leaving group such as halide, mesyl or        tosyl, by a standard procedure well known to those skilled in        the art. This is followed by treatment with alkali metal cyanide        by a known procedure. (Vogel's Textbook of Practical Org. Chem.,        5^(th) edition, 714).

The benzyl group of B-16 to B-18 can be removed by a known method suchas catalytic hydrogenolysis or by treatment with silyl iodideparticularly in those compounds wherein R^(F) is O, in a solvent such asCH₂Cl₂, CHCl₃, DMF, benzene, toluene, THF or dioxane, at ambient toreflux temperature for 2-18 hr.

-   -   (iv) The phenolic OH group formed by the removal of the benzyl        group in B-16 to

B-18 may be finally coupled with L-(CH₂)_(q)CR²³R²⁴COR²⁵ by a standardprocedure to afford the desired key intermediate B-20 (whereR^(A)═—(CH₂)_(p)CN).

Process 2-2 for the Preparation of Variants of Compound B-20 (R^(B) isCOR¹⁰, C₁-C₁₅-alkyl, halogen, OR¹⁰, SR¹⁰, S(O)R¹⁰ or S(O)₂R¹⁰, NO₂,NHC(O)R¹⁰, NHC(O)OR¹⁰, NHZ or NHTroc):

-   -   (i) The preparation of variants of compound B-13 (R^(B) is        COR¹⁰, OR¹⁰, SR¹⁰, S(O)R¹⁰ or S(O)₂R¹⁰)    -   The variants of compound B-13 may be prepared by functionalising        3-bromo-4-methylbenzoic acid by R^(B), wherein R^(B) has the        meaning as described above, in a manner similar to that        described in process 1-3 for the preparation of variants of        compound A-5.    -   (ii) The variants of compound B-13 may then be converted to the        desired variants of compound B-20 in a manner similar to that        described in the above process 2-1.        Process 2-3 for the Preparation of Compound B-20 Starting from        nitro 2-halobenzoic acid:    -   (i) Nitro substituted 2-halobenzoic acid may be esterified in a        manner similar to that described in the above process 2-1(i).    -   (ii) The halo group in the resulting ester may then be converted        to the cyano group according to the procedure described in        process 2-1(ii). Both the nitro and the cyano groups may then be        reduced under acidic conditions by any conventional method known        in the art, for example, catalytic hydrogenation as described in        the above process 2-1. The primary amino group can selectively        be protected using a suitable protecting group, such as Z, Boc,        Fmoc or Troc, to give B-14.    -   (iii) In yet another variation, the substituted 2-halo benzoate        ester may be treated with a reagent, such as        ZNH—CH₂CR⁸═CR^(C)-L, in the presence of a Pd- or Ni-based        catalyst. This can be followed by reduction of the nitro group        and double bond to give another variant of B-14. The reduction        of the double bond is optional.    -   (iv) Similarly, the substituted 2-halo benzoate ester may be        treated with R^(P)O—CR⁸═CR^(C)-L. Removal of the protecting        group (R^(P)) from the resulting enol ether will give a keto        compound. The keto compound may undergo reductive amination to        obtain a diamine. The amino group in the side chain may be        protected selectively, using reagents such as Z, Fmoc or Troc,        to give further variants of compound B-14.    -   (v) The variants of compound B-14 thus obtained may be subjected        to a Sandmeyer reaction in a manner similar to that described in        process 1-2 with the minor modification of carrying out said        reaction in a solvent medium of an organic solvent, such as THF,        dioxane or DMF, and water to obtain a compound designated as        B-15.    -   (vi) The compound B-15 may then be reacted with TFA-thioanisole        (J. C. S. Chem. Commun. 101, 1980) or any other standard reagent        used for deprotection such as 2N HBr in AcOH for the removal of        the Z group to obtain a compound designated as B-19.    -   (vii) The resulting compound B-19 may then be converted to the        desired key compound B-20 by alkylation followed by in situ        cyclization with compounds F-46 (R′ is L), G-53 (R′ is L),        H-63(R′ is L), H-71(R′ is L), and J-74. The symbol L represents        a leaving group, such as Cl, Br, I, OMes or OTs.

The synthesis of said fragments F-46, G-53, H-63, H-71 and J-74 areprovided hereinafter in processes 6-1, 7-1, 8-1 and 9-1, respectively.

Process 2-4 for the Preparation Variants of Compound B-20 Starting fromnitro 2-halobenzoic acid (R^(B) is C(O)R¹⁰, OR¹⁰, halogen, SR¹⁰, NO₂,NHCOR¹⁰ or NHCOOR¹⁰)

-   -   (i) The compound B-14 described above may be substituted with R⁸        (which is as described above) by the method described in process        1-3. For this, B-14 may be used in which the amino group        substituted on the phenyl ring may be in the unprotected or        protected (with groups, such as phthaloyl, Fmoc or Troc, which        are compatible with Z) form. (Protecting groups in Org        Synthesis, Ed, III, Green. T. W. and Wuts. P. G. M., John Wiley        & Sons Inc., p 494). Subsequent to the substitution of compound        B-14 with R^(B), any protecting group, such as phthaloyl, Fmoc        or Troc, may be removed by any conventional method.    -   (ii) The resulting amine may be subjected to a Sandmeyer        reaction as described in process 1-1 to obtain a cyano        derivative which on deprotection would result in another variant        of B-19.    -   (iii) The resulting compound may then be converted to the        desired variant of compound B-20 by alkylation with compounds        F-46 (R′ is L), G-53 (R′ is L), H-63 (R′ is L), H-71 (R′ is L),        and J-74, followed by in situ cyclization. The symbol L is as        described earlier.

The synthesis of said compounds F-46, G-53, H-63, H-71 and J-74 areprovided hereinafter in processes 6-1, 7-1, 8-1 and 9-1, respectively.

The key compounds A-8, B-20, A-9 and B-15 thus obtained may be subjectedto further reaction steps to obtain the compounds designated herein asC-22 and C-23; D-25, D-26, D-27 and D-28; and E-32 and E-33; whichcorrespond to the compounds of general formula (I), as described belowby the processes 3-1 to 5-1 and as schematically presented in Figures C,D and E, respectively.

Figure C

The preparation of compounds C-22 and C-23 by alternative reactionsequences is described below by the processes designated as process 3-1and process 3-2, which are schematically presented in Figure C:

Process 3-1 for the Preparation of Compounds C-22 and C-23:

-   -   (i) The cyano group in compound A-8 (R^(A)═—CN) or B-20        (R^(A)═NC(CH₂)_(p), where p is 0, 1-5) may be subjected to a        Pinner reaction to obtain the corresponding hydrochloride salt        of an imino ether which may then be treated with an appropriate        amino compound (substituted or unsubstituted) to obtain the        substituted or unsubstituted amidine compound designated as        C-21. Likewise the imino ether may be treated with a substituted        or unsubstituted hydroxylamine to obtain the corresponding        substituted or unsubstituted oxime designated as C-22.    -   Alternatively, the cyano group in compound A-8 (R^(A)═—CN) or        B-20 (R^(A)═NC(CH₂)_(p), where p is 0, 1-5) may be subjected to        a known reaction (Daniel. J., Sall. et. al. Bioorg. Med. Chem.        Lett. 6, 81, 1996 and reference therein) to obtain the        corresponding thioimidate compound which may then be treated        with an appropriate amino compound (substituted or        unsubstituted) or hydroxylamine to obtain the respective        substituted or unsubstituted amidino compound C-21 or the oxime        C-22.    -   Compounds of the present invention wherein the group R^(G) in        the compound C-23 (corresponding to compounds of general formula        (I)) is substituted by a group of formula 5 (defined        hereinabove) in which R²⁵ is OH may be obtained as follows: (1)        by subjecting an appropriately substituted oxime C-22 (R²⁵ is        OCH₂Ph) to acylation with Ac₂O(R²⁵ is OMe/OEt) followed by        hydrogenation (R²⁵ is OH) in accordance with a known procedure        (D. C., Batt. et. al. J. Org. Chem. 65, 8100, 2000), (2) by        hydrogenolysis of an appropriately substituted amidine C-21 (R²⁵        is OCH₂Ph), or (3) by first protecting the amidino group with an        appropriate group, preferably a Boc group, to give the compound        C-23 (R²⁵ is OMe/OEt, R³ is Boc) which may be subjected to        hydrolysis followed by deprotection of the amidino group (R²⁵ is        OH; R³ is H) using any conventional method known in the art.    -   A variant of compound C-22 (R¹&/or R⁴ is H, and R²⁵ is OH) may        be obtained by hydrolysis of an appropriately substituted        hydroxy amino compound C-22 (R¹ &/or R⁴ is H, and R²⁵ is OMe or        OEt) by LiOH in aqueous THF or NaOH or KOH in MeOH or a lower        alcohol.    -   Yet another variant of compound C-23 (R¹/R³/R⁴ is COOR⁵ or        COSR⁵) may be prepared by treating a suitably substituted        amidine C-21 (in which at least one of R¹, R³ and R⁴ in formula        3 as defined under general formula (I) represents H) with a        suitable chloroformate (R⁵OCOCl or R⁵SCOCl) or dicarbonate        ((R⁵OCO)₂O or (R⁵SCO)₂O).    -   Yet another variant of compound C-23, namely the N-sulphonyl or        N-acyl derivative of said compound, may be obtained by treating        a suitably substituted amidine C-21 (in which at least one of        R¹, R³ and R⁴ in formula 3 as defined under general formula (I)        represents H) with a suitable sulfonyl chloride or acyl        chloride, respectively.    -   Yet another further variant of compound C-23, namely the        carbonate, O-acyl or O-sulfonyl derivative of said compound, may        be prepared by treating the oxime C-22 (in which at least one of        R¹ or R⁴ in formula 3 as defined under general formula (I)        represents OH) with an appropriate reagent such as        chloroformate, acyl chloride or sulfonyl chloride.

Process 3-2 for the Preparation of Compounds C-22 and C23, Wherein theR^(A) Group Represents a Heterocyclic Ring:

-   -   The compound C-23 (R^(A) is 1,2,4-oxadiazole) may be prepared by        cyclizing compound C-22 (R¹ &/or R⁴ is H) with a suitable acid        anhydride, such as acetic anhydride, in accordance with a        reported procedure (Joachim Gante et al, Bioorg. Med. Chem.        Lett. 6, 2425, 1996) followed by hydrolysis.    -   Likewise, another compound corresponding to compound C-22 (R^(A)        is 5-oxo-4,5-dihydro-[1,2,4]oxadiazole) may be prepared by        treating the compound C-22 (R¹ &/or R⁴ is H) with a reagent such        as diethyl carbonate, carbonyl diimidazole, triphosgene or        phosgene by using a standard procedure known in the art.

Figure D

The preparation of compounds D-25 and D-28 by alternative reactionsequences is described below by the processes designated as process 4-1,which are schematically presented in Figure D:

Process 4-1 for the Preparation of Compounds Designated as D-25 to D-28

-   -   (i) The nitro group in the compound A-8 (R^(A) is NO₂) may be        subjected to reduction as described hereinbefore by using Zn and        CoCl₂ (Baruah. R. N., Ind. J. Chem., 33B, 758, 1994) to obtain        the corresponding amino compound designated as D-24.    -   (ii) The amino compound D-24 may be treated with a suitable        co-di-halogen compound under standard conditions known in the        art to give the compound designated as D-25, which corresponds        to a cyclic amino derivative.    -   (iii) The amino compound D-24 may also be substituted with a        desired alkyl group to give a compound designated as D-26.    -   (iv) The amino compound D-24 may further be treated with a        suitably substituted thioimidate salt (Ting Su et al, J. Med.        Chem., 40, 4308, 1997) to obtain a variant of the amidine        compound designated as D-28, in which R^(A) represents the group        of formula 4 (defined hereinabove).    -   The amidine compound D-28 wherein at least one of the groups R⁷        and R⁹ in formula 4 represents H, may further be functionalised        with groups such as urethan, N-acyl or N-sulfonyl by treating        with a suitable chloroformate, acyl chloride or sulfonyl        chloride, respectively, to obtain the desired variants of the        compound D-28.

Figure E

The preparation of compounds E-32 and E-33 by alternative reactionsequences is described below by the processes designated as process 5-1and process 5-2 which are schematically presented in Figure E:

Process 5-1 for the Preparation of Compounds Designated as E-32 and E-33Starting from Compound A-9:

-   -   (i) The 1,2,4-oxadiazole derivative designated as E-29 can be        obtained from compound A-9 by a procedure which is described in        process 3-2 above. The 1,2,4-oxadiazole derivative E-29 may be        treated with a compound designated as K-81 or K-83 using a        standard peptide coupling method, such as a DCC, mixed anhydride        method, to give the compound designated as E-32, wherein R^(G)        represents a heterocyclic ring.    -   (The preparation of compounds K-81 and K-83 are described        hereinafter in process 10).    -   (ii) Alternatively, the compound E-32 may be prepared by first        converting the derivative E-29 to an acid chloride designated as        E-30 and coupling the resulting acid chloride with compounds        designated as K-81 or K-83 in a manner similar to that described        in process 1-4.    -   (iii) Alternatively, a suitably substituted mono or polyhydroxy        phenol derivative may be subjected to a Friedel-Crafts acylation        with the acid chloride E-30 in a manner similar to that        described in process 1-4 to obtain yet another variant of        compound E-32 in which R^(G) represents an aryl or aromatic        heterocycle.    -   (iv) The variants of compound E-32 may be subjected to        hydrogenolysis to obtain an amidine designated as E-33.        Process 5-2 for the Preparation of Variants of Compounds E-32        and E-33 from the Compound B-15:    -   The cyano group in compound B-15 may be converted to        1,2,4-oxadiazole by the method described in the above process        3-2. The resulting compound is then subjected to a standard        deprotection procedure known in the art to remove the Z group to        obtain a compound designated as E-31. The resulting compound        E-31 may then be subjected to alkylation with F-46, G-53, H-62,        H-63 (wherein R′ is a leaving group, such as Cl, Br, I, OMes or        OTs) and 7-74, followed by in situ cyclization to obtain another        variant of compound E-32. The resulting compound E-32 may be        subjected to hydrogenation to obtain the amidine E-33.

Figure F

The preparations of variants of compound F-46 (used in the synthesis ofkey intermediates A-8 and B-20) via different synthetic routes aredescribed below by the processes designated as process 6-1, 6-2 and 6-3,which are schematically presented in Figure F. The groups R^(K), R^(L)and R^(V) in said compound F-46 represent substituents having the samemeaning as the ring substituents in the definition of R^(G). The group Rrepresents T (CH₂)_(q)CR²³R²⁴COR²⁵; R′ represents a H atom, a leavinggroup L, such as halogen, OMes or OTs, or a protected amino group, suchas NHZ; Hal is the halogen F, Cl, Br or I and the remaining groups areas defined earlier.

Process 6-1 for the Preparation of Variants of Compound F-46

-   -   (i) An appropriately substituted 1-(hydroxy-phenyl)ethanone may        be treated with L (CH₂)_(q)CR²³R²⁴COR²⁵ to obtain a compound        designated as F-46.    -   (ii) The compound F-46 thus obtained may then be treated with        chlorosulfonic acid followed by treatment with a suitable amine        R²¹R²²NH to get a variant of compound F-46 in which R^(L) and/or        R^(V) is SO₂NR²¹R²², wherein R^(L) and R^(V) are as defined        above.    -   (iii) The compound I-(hydroxy-phenyl)-ethanone may be        functionalised with a halogen through a standard nuclear        halogenation method; preferably using N-halosuccinimide in        solvents such as chloroform, dichloromethane, DMF, dioxane, THF,        acetonitrile or acetic, or a mixture of at least two of these        solvents, at from 0° C. to reflux temperature to obtain        compounds designated as F-39 and F-40, wherein R^(L) and R^(V)        each represent a halogen, independently selected from, for        example: Cl, Br and I.    -   (iv) The halogen substituted compounds F-39 and F-40 may be        converted to ether or thio ether derivatives designated herein        as F-41, wherein R^(L)/R^(V) are OR²¹ or SR²¹, according to a        reported procedure (Tetrahedron, 48, 3633, 1992; J. Org. Chem.,        62, 5413, 1997 and R. Adams et. al. J. Amer. Chem. Soc., 81,        4927, 1959).

(v) The thio ether F-41(R^(L)/R^(V) are SR²¹), may be oxidized to thesulfoxide or sulfone designated as F-42 (R^(L)/R^(V) are S(O)R²¹ orS(O)₂R²¹) with a suitable oxidizing agent well known to those skilled inthe art, preferably mCPBA, OXONE®, hydrogen peroxide or NaIO₄—Ru (IV).

-   -   (vi) The compounds F-39 to F-42 thus obtained may independently        be alkylated with L(CH₂)_(q)CR²³R²⁴COR²⁵ (wherein the groups        R²³, R²⁴, R²⁵ and the integer q are as defined earlier), using        standard reaction conditions to obtain variants of compound        F-46, wherein R is O(CH₂)_(q)CR²³R²⁴COR²⁵, R^(K) is H, and the        remaining groups are as defined earlier.        Process 6-2 for the Preparation of Variants of Compound F-46 in        which the Substituent R^(V) Contains a Nitrogen Atom and is        Connected to the Aromatic Ring Through N.    -   (i) An appropriately substituted 1-(hydroxy-phenyl)-ethanone is        nitrated by a standard procedure known in the literature or a        modification thereof, to give a compound designated as F-34,        which may be treated with L(CH₂)_(q)CR²³R²⁴COR²⁵ to obtain a        variant of the compound F-46, wherein R is        O(CH₂)_(q)CR²³R²⁴COR²⁵; R^(K) is H; R^(V) is NO₂; and the        remaining groups are as defined earlier.    -   (ii) The nitro group in compound F-34 may be subjected to        reductive acylation using catalytic hydrogenation in the        presence of an appropriate acid anhydride and a catalyst, such        as Raney Ni, or a noble metal (such as Pd or Pt) based catalyst,        to give a compound designated as F-43. F-43 may be subjected to        alkylation with L(CH₂)_(q)CR²³R²⁴COR²⁵ to obtain a variant of        the compound F-46, wherein R is O(CH₂)_(q)CR²³R²⁴COR²⁵; R^(K)        and R^(L) are H; R^(V) is NHCOR²²; and the remaining groups are        as defined earlier.    -   (iii) Alternatively, the OH group in compound F-34 may be        protected with a suitable protecting group (Protecting groups in        Org Synthesis, Ed, III, Green T. W. and Wuts. P. G. M, John        Wiley & Sons Inc., p 246), such as a benzyl group, to obtain a        compound designated as F-35. The compound F-35 may then be        subjected to nitro group reduction using any conventional        reduction method known in the art, for example, catalytic        reduction using Raney Ni or Zn—CoCl₂ in DMF (Baruah. R. N.        Ind. J. Chem., 33B, 758, 1994) to obtain an amino compound        designated as F-36. The amino compound F-36 may be treated with        an appropriate acyl chloride (R²¹COCl), sulfonyl chloride        (R²¹SO₂Cl), or chloroformate (R²¹OCOCl) followed by deblocking        of the benzyl group using any conventional method known in the        art to obtain a compound designated as F-37 in which R^(V) is        NHCOR²¹, NHSO₂NR²¹R²², or NHCOOR², respectively. The compound        F-37 may then be subjected to alkylation with        L(CH₂)_(q)CR²³R²⁴COR²⁵ to obtain yet another variant F-46,        wherein R is O(CH₂)_(q)CR²³R²⁴COR²⁵; R^(V) is NHCOR²¹,        NHSO²NR²¹R²² or NHCOOR²¹; R^(K) and R^(L) are H; and the        remaining groups are as defined earlier.        Process 6-3 for the Preparation of Variants of Compound F-46        from the Compound F-38:    -   (i) An appropriate 1-(halo-phenyl)-ethanone designated as F-38        may be subjected to nucleophilic displacement utilizing        HS(CH₂)_(q)CR²³R²⁴COR²⁵ either directly or through        Cu(I)-thiolate using a suitable modification of a reported        procedure (R. Adams et. al., J. Amer. Chem. Chem., 81,        4927, 1959) to obtain a variant of compound F-46, wherein R is        S(CH₂)_(q)CR²³R²⁴COR²⁵; and the remaining groups are as defined        earlier.    -   (ii) Alternatively, the compound F-38 may be subjected to a C—C        bond forming reaction, preferably vinyl coupling with        L-CH═CH(CH₂)_(q)CR²³R²⁴COR²⁵, wherein L is a halogen and q is        0-5, using a Pd- or Ni-based catalyst to give compound F-46.        F-46 may be hydrogenated to provide another variant of compound        F-46, wherein R is CH₂(CH₂)_(q)CR²³R²⁴COR²⁵; q is 1-6; and the        remaining groups are as defined earlier.

These variants of compound F-46 as prepared herein correspond to thecompounds of the present invention of the general formula (I), wherein Tin T-(CH₂)_(q)CR²³R²⁴COR²⁵ (formula 5) represents CH₂ or S.

Process 6-4 for the Preparation of Variants of Compound F-46 fromCompound F-44 or F-45

-   -   (i) An appropriately substituted di- or tri-hydroxy benzene may        be subjected to a Friedel-Crafts acylation with an anhydride,        such as R′(CH₂)_(n)CR^(D)R^(E)CO)₂O, or an acid chloride such as        R′(CH₂)CR^(D)R^(E)COCl, in the presence of a Lewis acid, such as        ZnCl₂, AlCl₃.HClO₄, BF₃.etherate, TiCl₄, FeCl₃ or I₂, and in a        solvent, such as CHCl₃, CH₂Cl₂, nitrobenzene or a C₆-C₁₄        hydrocarbon, at a temperature ranging from an ambient        temperature to 150° C., to obtain a compound designated as F-45.        Alternatively, the appropriately substituted di- or tri-hydroxy        benzene may be subjected to a Fries rearrangement with a phenol        ester of the type ArOCOCR^(D)R^(E)(CH₂)_(n)R′ or a Houben-Hoesch        acylation using a suitably substituted or unsubstituted nitrile        R′(CH₂)_(n), CR^(D)R^(E)CN according to a reported procedure        (Junkichi Murai, Chem. Abstr. 50 981c, 1950) to obtain the        compound F-45, wherein two or three of the groups R¹, R^(K),        R^(L) and K are OH and the remaining groups are as defined        earlier.    -   (ii) The resulting compound F-45 may be subjected to alkylation        with L(CH₂)_(q)CR²³R²⁴COR²⁵ to give the desired mono-, di- or        tri-alkylated products representing another variant of compound        F-46 wherein two or three of the groups selected from: R¹,        R^(K), R^(L) and R^(V) are —O(CH₂)_(q)CR²³R²⁴COR²⁵ and the        remaining groups are as defined earlier.    -   (iii) In an alternative approach, the appropriately substituted        polyhydroxy phenol may be alkylated first with LCH₂CR²³R²⁴COR²⁵        to obtain a compound designated as F-44, wherein two or three of        the groups selected from: R, R^(K), R^(L) and R^(V) are        —O(CH₂)_(q)CR²³R²⁴COR²⁵, and the remaining groups are as defined        earlier. The intermediate F-44 may be subjected to a        Friedel-Crafts acylation with [R′(CH₂)_(n)CR^(D)R^(E)CO)₂O] or        acid chloride [R′(CH₂)CR^(D)R^(E)COCl] in presence of a        catalyst, such as ZnCl₂, I₂, HClO₄ or, most preferably, Zn        powder (see Synth. Commun. 28, 2203, 1998) to obtain the desired        variants of the compound F-46.

These variants of compound F-46 as prepared herein correspond to thecompounds of the present invention of the general formula (I), in whichthe aromatic ring in R^(G) is substituted with at least twoT-(CH₂)CR²³R²⁴COR²⁵ groups.

Figure G

The preparation of variants of compound G-53 (used in the synthesis ofkey compounds A-8, E-32 and B-20) via different synthetic routes isdescribed below by the processes designated as process 7-1, which isschematically presented in Figure G. The groups R, R^(K), R^(L) andR^(V) in said compound G-53 and the remaining groups are as definedearlier.

Process 7-1 for the Preparation of Compound G-53:

-   -   (i) Unsubstituted or substituted 1-(2,4-dihydroxyphenyl)ethanone        may be subjected to various reactions similar to those described        in the above process 6-1, such as halogenation of the compound        1-(2,4-dihydroxyphenyl)ethanone to obtain the mono-substituted        compound designated as G-49 and the di-substituted compound G-50        (R^(L)/R^(V)=Cl/Br/I).    -   (ii) The compounds G-49 and G-50 may be converted into a ether        or a thioether derivative where R^(L)/R^(V)═OR²¹/SR²¹ in a        manner similar to that described in process 6-1 for the        conversion of compounds F-39 and F-40 to the compound designated        as F-41.    -   (iii) The thioether may be oxidized to a sulfoxide or sulfone        where R^(L)/R^(V) is S(═O)R²¹ or S(═O)₂R²¹ with a suitable        oxidizing agent.    -   (iv) The unsubstituted or appropriately substituted        1-(2,4-dihydroxy-phenyl)ethanone may be subjected to a        Friedel-Crafts alkylation to obtain the compound designated as        G-48, wherein R^(K) is OH.    -   (v) Friedel-Crafts acylation of G-47 (which is obtained by the        reduction of 1-(2,4-dihydroxy-phenyl)ethanone by a standard        procedure) or an appropriately substituted polyhydroxy phenol,        such as substituted resorcinol or trihydroxy phenol, with a        suitable anhydride, such as (R′(CH₂)_(n), CR^(D)R^(E)CO₂)O, or a        suitable acid chloride, such as R′(CH₂)_(n)CR^(D)R^(E)COCl,        gives the compounds designated as G-48 and G-54. Alternatively,        the compound G-47 or an appropriately substituted polyhydroxy        phenol may be subjected to a Houben-Hoesch acylation with        R′(CH₂)_(n)CR^(D)R^(E)CN to give the compounds designated as        G-48 or G-54, wherein R^(K) is OH and the remaining groups are        as defined earlier.    -   (vi) The Claisen rearrangement of phenolic allyl ether G-56,        wherein R^(a), R^(b), R^(c), R^(d) and R^(e) are independently        selected from: C₁-C₅ alkyl and C₇-C₁₂ alkylaryl, resulted in        G-57. The double bond reduction of G-57 according to a standard        procedure well known in the art gives compound G-58, wherein its        groups are as defined earlier.    -   (vii) The compounds G-54 and G-58 may be reduced partially or        fully by a standard procedure to give the compound designated as        G-55, wherein R^(F) is (H, OH) or (H, H) and the remaining        symbols are as defined.    -   (viii) All the compounds G-48 to G-52, G-54, G-55, G-58 as well        as 1-(2,4-dihydroxy-phenyl)ethanone, are treated with        L-(CH₂)_(q)CR²³R²⁴COR²⁵ using a standard procedure to give a        variant of compound G-53, wherein R^(K) is OH; one or more of        the groups R, R^(L) and R^(V) represent O(CH₂)_(q)CR²³R²⁴COR²⁵;        and the remaining groups are as defined earlier.    -   (ix) The compounds G-53 in which R^(K) is OH, may be further        subjected to substitution reactions using an appropriate alkyl        halide, acyl halide, sulfonyl chloride or chloroformate, to        obtain variants of compound G-53, wherein R^(K) is OCOR²¹,        OS(═O)₂R²¹ or —OCOOR²¹; one or more of the groups R, R^(L) and        R^(V) are O(CH₂)_(q)CR²³R²⁴COR²⁵; and the remaining symbols are        as defined earlier.

Figure H

The preparation of variants of compounds H-63, H-71 and H-72, whereinR^(K) and/or R^(U) are/is OH or substituted OH (used in the synthesis ofkey intermediates A-8, B-20 and E-32) via different synthetic routes isdescribed below in the processes designated as 8-1 and 8-2, which areschematically presented in Figure H.

Process 8-1 for the Preparation of Compound H-63 and its Variants:

-   -   (i) An appropriately substituted dihydroxy benzaldehyde, such as        3,4-dihydroxy benzaldehyde, may be subjected to a sequence of        reaction steps such as alkylation with L(CH₂)_(q)CR²³R²⁴COR²⁵ to        obtain the compound designated as H-59, wherein R is        O(CH₂)_(q)R²³R²⁴COR²⁵. The compound H-59 may then be subjected        to a Baeyer-Villiger oxidation (I. M. Godfrey et. al, J. C. S.        Perkin I, 1353, 1974) followed by hydrolysis of the resulting        formyl ester and subsequent alkylation of phenolic OH to obtain        the compound designated as H-60, wherein R^(a), R^(b) and R^(c)        are independently selected from: C₁-C₅ alkyl and C₇-C₁₂ alkyl        aryl.    -   (ii) The compound H-60 may be subjected to a Friedel-Crafts        acylation (H. M. Meshram. et. al., Synth. Commun, 28,        2203, 1998) with R′(CH₂)_(n)CR^(D)R^(E)COCl in the presence of a        Lewis acid catalyst, such as Zn, BF₃.etherate, FeCl₃, AlCl₃ and        ZnCl₃, preferably Zn, in the presence of at least one organic        solvent selected from, for example: toluene, benzene, heptane,        kerosene, CS₂, CCl₄, and nitrobenzene, preferably toluene, and        in situ cleavage of the allyl group to obtain the desired        compound H-63, wherein R and R^(V) are O(CH₂)_(q)CR²³R²⁴COR²⁵;        R^(k) is OH; R^(L) is H; R^(F) is O; and the remaining groups        are as defined earlier.    -   (iii) A variant of compound H-63 (wherein R^(K) represent OR²¹,        OCOR²¹, OS(═O)₂R²¹ or OCOOR²¹, and the remaining groups are as        defined earlier) may be obtained by treatment of the compound        H-63, wherein R^(K) is OH, with an appropriate alkyl halide,        acyl halide, sulfonyl halide or chloroformate under standard        reaction conditions well known in the art.    -   (iv) Yet another variant of compound H-63, wherein R and R^(V)        represent O(CH₂)_(q)CR²³R²⁴COR²⁵; R^(F) is (H, H); R^(D) and        R^(E) are H; and the remaining groups are as defined earlier,        may be prepared by subjecting the compound H-59 to a Wittig        reaction to obtain the compound designated as H-64 which on        hydrogenation gives the desired variant.    -   (v) An appropriately substituted        1-(2,5-dihydroxy-phenyl)-ethanone may be alkylated with        L-(CH₂)_(q)CR²³R²⁴COR²⁵ to give a variant of compound H-63        (wherein R is H; R^(V) is O(CH₂)_(q)CR²³R²⁴COR²⁵; R^(F) is O;        and the remaining groups are as defined earlier).    -   (vi) Another variant of compound H-63 may be obtained by        subjecting the compound H-60 to a Friedel-Crafts alkylation with        R′(CH₂)_(n)CR^(D)R^(E)CH₂L, wherein R′ is H, NHZ or L and L is a        leaving group, such as halogen, OMes or OTs, to obtain the        compound designated as H-61, followed by the removal of the        allyl group from the resulting compound H-61 to obtain another        variant of compound H-63, wherein R^(F) represents (H, H); R and        R^(V) are O(CH₂)_(q)CR²³R²⁴COR²⁵; R^(K) is OH; and the remaining        groups are as defined earlier.    -   (vii) Yet another variant of compound H-63 may be obtained by        reducing the carbonyl group in compound H-63 (wherein R^(F)        is O) by a standard procedure known in the art to give compound        H-63, wherein R^(F) represents (H, OH) or (H, H), and the        remaining groups are as defined earlier.    -   (viii) The allyl group in compound H-61 may be removed by a        standard method to give the compound designated as H-62, wherein        R^(F) is (H, H). The compound H-62 may be subjected to a        substitution reaction with an appropriate alkyl halide, acyl        halide or chloroformate leading to the formation of a variant of        the compound H-63, wherein R^(F) is (H, H); R^(K) represents        OR²¹; OCOR²¹; OCOR²¹; OS(═O)₂R²¹ or OCOOR²¹; and the remaining        groups are as defined earlier.        Process 8-2 for the Preparation of Variants of Compound H-71 and        H-72 (wherein R^(K) and/or R^(U) are/is OH or Substituted OH):    -   (i) Phloroglucinol may be subjected to O-alkylation (Chem.        Abstr., 50, 977d, 1956) to obtain 5-methoxy-1,3-benzenediol,        designated as H-65.    -   (ii) Alternatively, phlororoglucinol may be converted to        5-benzyloxy-1,3-benzenediol designated as H-68 by following a        sequence of reactions according to a reported procedure (Haruo.        Kawamoto. et. al., Synth. Commun. 26, 531, 1996).    -   (iii) The compounds H-65 and H-68 thus obtained may be subjected        to a novel modification of the Houben-Hoesch reaction in which a        suitably protected amino nitrile of the type        R′(CH₂)_(n)CR^(D)R^(E)CN, wherein R¹ is H, NHZ or L, and L is a        leaving group, such as halogen, OMes or OTs, may be treated with        dry HCl in presence of a Lewis acid, such as ZnCl₂ or        BF₃.etherate, in a solvent, such as ether, THF or dioxane,        followed by hydrolysis of the resulting imine hydrochloride to        obtain the compound designated as H-69, wherein its groups are        as defined earlier.    -   (iv) The compound H-69 may be subjected to selective alkylation        with L-(CH₂)_(q)CR²³R²⁴COR²⁵, wherein L is a leaving group, such        as halogen, OMe-s or OTs, to give the compound designated as        H-70, wherein R is O(CH₂)_(q)CR²³R²⁴COR²⁵, and the remaining        groups are as defined earlier.    -   (v) The compound H-70 may be subjected to further reactions such        as O-alkylation, O-sulphonation, O-acylation or carbonate        formation reaction as described earlier resulting in variants of        the compound H-70 designated as H-71, wherein R^(U) represents        OR²¹, OCOR²¹, OS(═O)₂R²¹ or OCOOR²¹; and the remaining groups        are as defined earlier.    -   (vi) The compound H-71 in which R¹ is NHZ and optionally R^(K)        is OCH₂Ph may be subjected to a standard deblocking reaction        known in the art, to obtain the amino compound designated as        H-72, wherein B is halogen, acetate or formate.

Figure J

The preparation of compounds J-74 and J-77 (used in the synthesis of keyintermediates A-8, B-20 and E-32) via different synthetic routes isdescribed below by the processes designated as process 9-1, which isschematically presented in Figure J. In the compounds referred to below,the groups R′, R^(F), R^(D), R^(E), and n are as described earlier. R isT(CH₂)_(q)CR²³R²⁴COR²⁵ or OCH₂Phenyl and R^(K), R^(L), R^(U) and R^(V)are independently selected from the substituent groups provided in thedefinition of R^(G).

Process 9-1 for the Preparation of Compounds J-74 and J-77

-   -   (i) Appropriately substituted compounds F-46, G-53, H-63, H-70        and H-71 (in all these compounds n is 0, R′═R^(D)═R^(E)═H)        (prepared by processes described hereinabove) may be subjected        to a standard α-bromination reaction, most preferably by using        bromine in an appropriate solvent, for example, an organic        solvent such as, optionally in the presence of a catalyst, such        as AlCl₃ or other Lewis acid, to obtain the mono-bromo compound        designated as J-74. Alternatively, the bromination may be        carried out using CuBr₂ according to a known precedure (L C.        King. et. al., J. Org. Chem., 29, 3459, 1964), leading to the        formation of the mono bromo compound J-74.    -   (ii) The mono-bromo derivative J-74 may then be converted to a        hexamine salt according to a reported procedure (L. M. Long. et        al J. Amer. Chem. Soc., 71, 2473, 1949) which may in turn be        subjected to a cleavage reaction using an aqueous acid        optionally in presence of a lower alcohol, such as MeOH, EtOH,        or iPrOH, to obtain the amine hydrochloride designated as J-77,        and a small amount of acid (R²⁵ is OH) as a side product,        wherein R^(F) is O; R^(D) and R^(E) are H; n is 0; and the        remaining groups are as described.    -   (iii) The compound J-77, if required, may be purified by        treating the mixture of the compound and the residual acid with        a suitable reagent, such as (Boc)₂O, for protecting the amino        group in an alkaline condition to obtain the separated compounds        designated as J-75 (wherein R^(F) is O; R^(D) and R^(E) are H; n        is 0) and J-76, (wherein R^(F) is O; R^(D) and R^(E) are H; n is        0; and R and/or R^(V)=T(CH₂)_(q)CR²³R²⁴COOH). Deprotection of        the compound J-75 may be carried out using a standard        deprotecting reagent known in the art of peptide synthesis to        obtain the desired compound J-77.    -   (iv) Likewise, the other compound J-76 (wherein R²⁵ is OH) may        be converted to its corresponding ester by treatment with R⁵OH        or R⁵SH, in the presence of DCC and DMAP according to a reported        procedure (Alfred. Hassner. et. al. Tetrahedron Lett.        4475, 1978) to obtain a variant of the compound J-75, wherein R        is O(CH₂)_(q)CR²³R²⁴COR²⁵, and R²⁵ is OH.    -   (v) Alternatively, the compound J-76 in which R²⁵ is OH may be        converted to an amide by treatment with an appropriate amine of        formula R⁵R⁶NH in which R⁵ and R⁶ are as defined, using a        standard peptide coupling procedure resulting in a variant of        the compound J-75.    -   (vi) Deprotection of the Boc group of the compound J-75 may be        carried out using formic acid, TFA or HCl in an organic solvent        in presence of anisole or thioanisole to give the compound J-77,        wherein R^(F) is O; R^(D) and R^(E) are H; n is 0; and the        remaining groups are as defined earlier.    -   (vii) Alternatively, the compounds F-46, G-53, H-63, H-70 and        H-71 [wherein R′ is L and R^(F) is O or (H, H)] may be converted        to a hexamine salt (see L. M. Long. et al J. Amer. Chem. Soc.,        71, 2473, 1949), which may be subjected to cleavage using        aqueous acid, optionally in presence of a lower alcohol, such as        MeOH, EtOH or iPrOH, to obtain the corresponding amine        hydrochloride J-77. Purification of said amine hydrochloride, if        required, may be carried out by treating the mixture of compound        J-77 and acid with a suitable reagent such as (Boc)₂O for        protecting the amino group in an alkaline condition to obtain        the compound J-73, wherein R^(F) is O or (H, H); and the        remaining groups are as defined earlier.    -   (viii) Deprotection of the compound J-73 may be carried out        using a standard deprotecting reagent known in the art of        peptide synthesis to obtain the compound J-77, wherein R^(F) is        O or (H, H) and the remaining groups are as defined earlier.    -   (ix) Further, if required, functional group modification such as        alkylation, acylation, sulphonation or carbonate formation may        be carried out on the OH, SH and/or NHR²¹ group(s) of the        compound J-75, wherein one or more of the groups R^(K), R^(L),        R^(U) and R^(V) independently represent OH, SH or NHR²¹ to        obtain the desired variant of the compound, wherein one or more        of the groups R^(K), R^(U) and R^(V) independently represent        OR²¹, SR²¹ or NR²¹R²².    -   (x) The thus obtained intermediate J-75 may be subjected to        deprotection of the Boc group leading to the formation of the        variant of compound J-77, wherein all its groups are as defined        earlier.    -   (xi) Variants of the compound J-75, wherein one or more of the        groups R^(K), R^(L) R^(V) and R^(U) represent SR²¹, may be        subjected to functional group modification, such as oxidation of        the thiol ether to give a variant of compound J-75, wherein one        or more of the groups R^(K), R^(L) R^(V) and R^(U) represent        S(═O)R²¹ or S(═O)₂R²¹, which may further be subjected to Boc        deblocking leading to the formation of variant J-77, wherein all        its groups are as defined earlier.    -   (xii) Variants of the compound J-75, wherein one or more of the        groups R^(K), R^(L) R^(V) and R^(U) represent NO₂, may be        subjected to reduction to obtain the corresponding amine, which        may further be treated with an appropriate acyl halide, sulfonyl        halide or chloroformate to give a variant of compound J-75,        wherein one or more of the groups R^(K), R^(L)R^(V) and R^(D)        represent NHCOR²¹, NHSO₂R²¹ or NHCOOR²¹, which in turn may be        subjected to removal of the Boc group leading to the formation        of variant compound J-77, wherein all its groups are as defined        earlier.    -   (xiii) Yet another approach for the preparation of a variant of        the compound J-77, wherein R^(F) is O; R^(D) and R^(E) are H; n        is 0; R is OCH₂Ph; and the remaining symbols are as defined        earlier, may involve the preparation of a compound designated as        J-78 from an appropriately substituted        1-(hydroxy-phenyl)ethanone through phenolic OH group protection        (preferably by a benzyl group) followed by the similar sequence        described earlier. After deprotection of the benzyl group, the        phenolic OH group may be alkylated with L-(CH₂)_(q)CR²³R²⁴COR²⁵        to obtain the compound J-75. Finally, both compounds J-75 and        J-78 may be subjected to removal of the Boc group to obtain        variants of the compound J-77. The compound J-77 in which R is        OCH₂Ph is used in the synthesis of fragment B-20.

Figure K

The preparation of compounds K-81, K-83, and K-84 (used in the synthesisof key intermediates A-8 and E-32) via different synthetic routes isdescribed below by the process designated as process 10-1, which isschematically presented in Figure K. The groups n, R^(D), R^(E), q and Tin said compounds have the same meaning as described for the generalformulae (I) and Q represents CH or N.

Process 10-1 for the Preparation of Compounds K-81, K-83 and K-84:

-   -   (i) N-Protected 4-hydroxy piperidine may be treated with        L(CH₂)_(q)CR²³R²⁴COR²⁵ in which L and q are as defined earlier,        to obtain a compound designated as K-79, wherein T is O.    -   (ii) The hydroxy group of the N-protected 4-hydroxy piperidine        may be converted into a suitable leaving group, such as OMes or        OTs, followed by treatment with an amine of the type        H₂N(CH₂)_(q)CR²³R²⁴COR²⁵ or a thiol of the type        HS(CH₂)_(q)CR²³R²⁴COR²⁵ to give a variant of compound K-79,        wherein T is NH or S.    -   (iii) Another variant of the compound K-79, wherein T is —CH₂—,        may be obtained by catalytic hydrogenation of the corresponding        pyridine derivative, preferably using PtO₂ in acetic acid, to        obtain an amine followed by protection of the resulting amine        with a suitable protecting group such as Boc or Z.    -   (iv) Alternatively, isonicotinic acid may be reduced to        isonipecotic acid according to a reported procedure (U.S. Pat.        No. 7,399,68), which after N-protection with a suitable        protecting group, preferably Z or Boc, may be converted to an        aldehyde designated as K-80 according to a reported procedure        (M. S. Egbertson et al, J. Med. Chem., 37, 2537, 1994). The        aldehyde may then be treated with an appropriate Wittig reagent        to obtain a variant of compound K-79, wherein T(CH₂)_(q)        represents —CH═CH(CH₂)_(q-1). The double bond may be subjected        to any conventional reduction method known in the art,        preferably hydrogenation resulting in a variant of compound        K-79, wherein T is —CH₂—.    -   (v) The removal of the Z or Boc group may be carried out using a        standard procedure known in the art to obtain a compound        designated as K-81, wherein all its groups are as defined        earlier.    -   (vi) Commercially available piperazine or its derivatives may be        converted to a compound designated as K-83, in a similar manner        as described above in this process. A final deprotection step to        remove the Boc or Z group with an appropriate deprotecting        reagent known in the art provides the amino compound K-83.    -   (vii) Compounds K-83 and K-81 may be coupled with a suitably        protected amino acid, such as Z- or        Boc-NH(CH₂)_(n)CR^(D)R^(E)COOH (wherein the symbols are as        defined earlier), using a standard peptide coupling method,        preferably DCC-HOBt or IBCF-NMM, to obtain the compound        designated as K-82, which may be further subjected to a standard        Boc or Z deprotection to obtain the compound K-84, wherein Q is        CH or N; and the remaining groups are as defined earlier.

The compounds K-81, K-83, and K-84 obtained by the above process arerequired for the preparation of compounds of general formula (I), inwhich R^(G) represents substituted piperidine and substitutedpiperazine.

Compounds according to the general formula (I) can be used to antagonizethe activity of GP IIb/IIIa receptors and are beneficial pharmaceuticalcompounds for the treatment of various thrombotic diseases. In thecontext of the present invention, compounds of this invention may beadministered to patients, where prevention of thrombosis by inhibitingthe binding of fibrinogen to the platelet membrane glycoprotein complexGPIIb/IIIa receptor is desired. This would include patients withcardiovascular (arterial and/or venous) and cerebrovascularthromboembolic diseases, under which the following can be included(though are not limited to):

1. arterial thromboembolism2. cerebral thromboembololism3. cerebral arterial thrombosis4. coronary thrombosis5. deep vein thrombosis6. diabetes-related thromboembolic disorders7. sudden ischemic emergencies8. myocardial infarction9. pulmonary thromboembolisms10. stroke11. thrombophlebitis12. transient ischemic attack13. unstable angina and venous thrombosis14. kidney thromboembolism

These compounds are useful during surgery on peripheral arteries(arterial grafts, carotid endarterectomy) and cardiovascular surgerywhere manipulation of arteries and organs, and/or the interaction ofplatelets with artificial surfaces, such as surgical instruments and theheart-lung machine leads to platelet aggregation. The aggregatedplatelets may form thrombi and thromboemboli. Compounds of thisinvention may be administered to these surgical patients to prevent suchcomplications. (S. D. Berkowitz, American Heart Journal, 2001, 142,7-13).

Extracorporeal circulation is routinely used for cardiovascular surgeryin order to oxygenate blood. Platelets adhere to surfaces of theextracorporeal circuit. Adhesion is dependent on the interaction betweenGP IIb/IIIa receptors on the platelet membranes and fibrinogen adsorbedto the surface of the circuit (Gluszko et al., Am. J. Physiol., 1987,252(H), 615-621,). Platelets released from an artificial surface showimpaired hemostatic function. Compounds of this invention may beadministered to prevent this adhesion.

Other applications of these compounds include (though are not limitedto):

-   1. prevention of platelet thrombosis-   2. thromboembolism and reocclusion during and after thrombolytic    therapy and prevention of platelet thrombosis-   3. thromboembolism and reocclusion after angioplasty or coronary    artery bypass surgery-   4. prevention of myocardial infarction-   5. prevention of blood clots after orthopedic surgery

Cell adhesion (cell-cell or cell-matrix) involves processes that requireproteins like fibrinogen, fibronectin, vitronectin and vWF. Theseproteins bind to the integrin superfamily of receptors to produce theiraction. Thus, GP IIb/IIIa antagonists which antagonize the integrinsuperfamily of receptors may be useful in diseases, other than theabove, which involve cell adhesion processes. Such diseases include(though are not limited to):

1. adult respiratory distress syndrome2. allergies3. asthma4. rupture of atherosclerotic plaques5. autoimmune diseases6. inflammation,7. bone degradation8. contact dermatitis9. diabetic retinopathy10. eczema11. graft versus host disease12. inflammatory bowel disease13. metastasis14. organ transplantation rejection15. osteoarthritis16. osteoporosis17. psoriasis18. rheumatoid arthritis19. septic shock20. tumors

The present invention therefore also relates to the compounds of thegeneral formula (I) and/or their pharmaceutically acceptable saltsand/or their pro-drugs for use as pharmaceuticals (or medicaments), tothe use of the compounds of the general formula (I) and/or theirphysiologically tolerable salts and/or their pro-drugs for themanufacture of medicaments for the production of pharmaceuticals for theinhibition of GP IIb/IIIa receptors or for the therapy or prophylaxis ofthe diseases and conditions mentioned above, for example for theproduction of pharmaceuticals for the therapy and prophylaxis ofcardiovascular (arterial and/or venous) and cerebrovascularthromboembolic diseases, etc., and to methods of treatment aiming atsuch purposes including methods for said therapies and prophylaxes. Themethods of treatment comprise administering a compound of generalformula (I) and/or its physiologically tolerable salts and/or itspro-drugs to a mammal, especially a human. The present inventionfurthermore relates to pharmaceutical compositions that contain aneffective amount of at least one compound of the general formula (I)and/or its physiologically tolerable salts and/or its prodrugs inaddition to a customary pharmaceutically acceptable carrier, and to aprocess for the production of a pharmaceutical, which comprises bringingat least one compound of general formula (I) into a suitableadministration form using a pharmaceutically suitable andphysiologically tolerable excipient and, if appropriate, furthersuitable active compounds, additives or auxiliaries. The pharmaceuticalpreparation comprises the compound of general formula (I) in an amountadequate to antagonize GP IIb/IIIa receptors. The present invention alsorelates to a method for the preparation of a medicament for thetreatment or prevention of disorders associated with activation of GPIIb/IIIa receptors, characterized in that at least one compound of thegeneral formula (I) is used as the pharmaceutically active substance.

The pharmaceuticals can be administered orally, for example in the formof pills, tablets, coated tablets, capsules, granules or elixirs.Administration, however, can also be carried out rectally, for examplein the form of suppositories, or parentally, for example intravenously,intramuscularly or subcutaneously, in the form of injectable sterilesolutions or suspensions, or topically, for example in the form ofsolutions or transdermal patches, or in other ways, for example in theform of aerosols or nasal sprays or as precoated stents.

The pharmaceutical preparations according to the invention are preparedin a manner known per se and familiar to one skilled in the art.Pharmaceutically acceptable inert inorganic and/or organic carriersand/or additives can be used in addition to the compound(s) of thegeneral formula (I) and/or its (their) physiologically tolerable saltsand/or its (their) prodrugs. For the production of pills, tablets,coated tablets and hard gelatin capsules it is possible to use, forexample, lactose, corn starch or derivatives thereof gum arabic,magnesia or glucose, etc. Carriers for soft gelatin capsules andsuppositories are, for example, fats, waxes, natural or hardened oils,etc. Suitable carriers for the production of solutions, for exampleinjection solutions, or of emulsions or syrups are, for example, water,physiological sodium chloride solution or alcohols, for example,ethanol, propanol or glycerol, sugar solutions, such as glucosesolutions or mannitol solutions, or a mixture of the various solventswhich have been mentioned.

The pharmaceutical preparations normally contain about 1 to 99%,preferably about 5 to 70%, most preferably from about 10 to about 30% byweight of the compounds of the general formula (I) and/or theirphysiologically tolerable salts and/or their prodrugs. The amount of theactive ingredient of the general formula (I) and/or its physiologicallytolerable salts and/or its prodrugs in the oral pharmaceuticalpreparations normally is from about 5 to 200 mg. The dose of thecompounds of this invention, which is to be administered, can cover awide range. The dose to be administered orally daily is to be selectedto suit the desired effect. About 10 to 100 mg are preferablyadministered orally daily per patient. If required, higher or lowerdaily doses can also be administered. For intravenous administration themost preferred dose will range from about 0.01 to 3 mg per patient.Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective in achieving the desiredtherapeutic response for a particular patient, composition and mode ofadministration without being toxic to the patient. The effective amountof a compound of the present invention, which may be administered in asingle dose or in the form of individual divided doses, may bedetermined by one of ordinary skilled in the art. It will be understoodthat the specific dose level and frequency of dosage for any particularsubject may be varied and will depend upon a variety of factorsincluding the activity of the specific compound employed, the metabolicstability and length of action of that compound, the species, age, bodyweight, general health, sex and diet of the subject, the mode and timeof administration, rate of excretion, drug combination, and severity ofthe particular condition.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, the route of administration, the time ofadministration, the rate of excretion of the particular compound beingemployed, the duration of the treatment, other drugs, compounds and/ormaterials used in combination with the particular compounds employed,the age, sex, weight, condition, general health and prior medicalhistory of the patient being treated, and like factors well known in themedical arts.

In addition to the active ingredients of the general formula (I) and/ortheir physiologically acceptable salts and/or prodrugs and to carriersubstances, the pharmaceutical preparations can contain additives suchas, for example, fillers, antioxidants, dispersants, emulsifiers,defoamers, flavor corrigants, preservatives, solubilizers or colorants.They can also contain two or more compounds of the general formula (I)and/or their physiologically tolerable salts and/or their prodrugs.Furthermore, in addition to at least one compound of the general formula(I) and/or its physiologically tolerable salts and/or its prodrugs, thepharmaceutical preparations can also contain one or more othertherapeutically or prophylactically active ingredients.

The compounds of the present invention may be used as drugs in thetreatment of thrombotic diseases either alone or as part of combinedtherapies. For instance, the compounds of the present invention may beused in combination with known antithrombotic agents. If formulated as afixed dose, such combination products employ the compounds of thepresent invention within the dosage range described above and the otherpharmaceutically active agent within its approved dosage range. Forexample, in the 2^(nd) SYMPHONY trial patients were treated withsibrafiban and aspirin. In the NICE-4 trial, a combination of abciximaband enoxaparin was studied (Bhatt, D. L. and Topol, E. J., JAMA, 2000,284, 1549-1558).

It is understood that modifications that do not substantially affect theactivity of the various embodiments of this invention are includedwithin the invention disclosed herein. Accordingly, the followingexamples are intended to illustrate but not to limit the presentinvention.

The examples as described below are given by way of illustration onlyand are not to be construed as limiting the invention in any way in asmuch as many variations of the invention are possible within the meaningof the invention.

Example 1(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester, acetic acid salt

A solution of the compound of example 1i (1.49 g; 2.76 mmol) in MeOH (40ml) was treated with ammonium acetate (0.86 g; 11 mmol), refluxed for 1h, concentrated, purified using flash chromatography (RP-18 column,MeOH: 0.2% AcOH in water/1:1) and crystallized using dry MeOH-ether toobtain the title compound. Yield, 0.08 g (6.6%); mp, 181-182° C.; MS(ESI): 404 (M⁺+Na⁺), 382 (M⁺+1); analysis: C₂₂H₂₃N₃O₇, 0.5H₂O requires,C, 58.66; H, 5.55; N, 9.33. found: C, 58.31; H, 5.23; N, 9.72%.

Example 1a 2-Methyl-4-nitro-benzoic acid ethyl ester

Thionyl chloride (48 ml) was added slowly to 2-methyl-4-nitro-benzoicacid (85 g; 0.469 mol) and the reaction mixture was refluxed (4-6 h) togive a clear solution. It was brought to room temperature then chilledto 0° C. Dry alcohol (150 ml) was added slowly with vigorous stirringand the reaction mixture was refluxed for 30 min. It was concentrated,treated with crushed ice, NaHCO₃ and extracted with EtOAc. The EtOAclayer was washed with water, brine, dried (Na₂SO₄), concentrated,purified using flash chromatography (silica gel, 10% EtOAc-PE 60-80° C.)and crystallized using EtOAc-PE 60-80° C. to obtain the title compoundas light yellow crystals. Yield, 83.8 g (85.4%); mp, 68-71° C.; IR:2950, 1720, 1525; MS (EI): 209(M⁺), 192. 181, 163 (100%), 89.

Example 1b 4-Amino-2-methyl-benzoic acid ethyl ester

Compound of example 1a (41 g; 196 mmol) in MeOH (500 ml) washydrogenated using Raney Ni (2 g) at 50 psi for 2 h. The solution wasfiltered free off the catalyst, concentrated and purified using flashchromatography (silica gel, 10% EtOAc-PE 60-80° C., 30% EtOAc-PE 60-80°C.) to obtain the title compound. Yield, 33 g (93.94%); mp, 77-80° C.,MS (EI): 179 (M⁺), 134 (100%), 106, 77; analysis: C₁₀H₁₃NO₂ requires, C,67.02; H, 7.31; N, 7.82. found, C, 67.25; H, 7.26; N, 7.57%.

Example 1c 4-Cyano-2-methyl-benzoic acid ethyl ester

Compound of example 1b (32 g; 178 mmol) was treated with conc. HCl (64ml) and water (320 ml), cooled to 0° C., then treated to a dropwiseaddition of an aqueous solution of NaNO₂ (12.33 g; 178 mmol, 320 ml)over a period of 1 h at 0-5° C. The diazonium salt solution wasneutralized with Na₂CO₃ and added slowly to an aqueous solution of KCNand CuCN (13.38 g; 204.4 mmol, 19.34 g; 204.4 mmol, 500 ml), maintainedat 0-5° C., with vigorous stirring over a period of 1 h. The reactionmixture was stirred for 30 min. at 0-5° C. and left stirring overnightat room temperature. It was subsequently heated on steam bath for 30min., treated with an aqueous 10% FeCl₃ solution and extracted withEtOAc (3×500 ml). The organic layer was washed with water, brine, dried(Na₂SO₄), concentrated, purified using flash chromatography (silica gel,5% EtOAc-PE 60-80° C.) and crystallized using EtOAc-PE 60-80° C. toobtain the title compound as a pure white solid. Yield, 20 g (59.2%);mp, 64-65° C.; MS (EI): 189 (M⁺), 144 (100%), 116, 89; analysis:C₁₁H₁₁NO₂, 0.5H₂O requires C, 66.70; H, 6.06; N, 7.07. found: C, 67.11;H, 5.88; N, 6.88%.

Example 1d 2-Bromomethyl-4-cyano-benzoic acid ethyl ester

NBS (22.8 g; 128 mmol) was added to a solution of the compound ofexample 1c (22 g; 116.4 mmol) in CCl₄ (1 lit.), followed by a catalyticamount of AIBN (˜10 mg). The reaction mixture was refluxed (6-7 h),cooled to room temperature, washed with water, brine, dried (Na₂SO₄),concentrated, purified using flash chromatography (5% EtOAc-PE 60-80°C.) and crystallized using EtOAc-PE 60-80° C. to obtain the titlecompound. Yield, 15.8 g (50.64%); mp, 70-72° C.; analysis: C₁₁H₁₀BrNO₂,0.5H₂O requires C, 49.25; H, 3.73; N, 5.22. found: C, 49.27; H, 3.62; N,4.79%.

Example 1e (4-{2-Amino-acetyl}-phenoxy)-acetic acid methyl ester,hydrochloride Example 1f(4-{2-tert-Butoxycarbonylamino-acetyl}-phenoxy)-acetic acid

Hexamine (7.56 g; 54 mmol) was added with stirring to a solution of(4-{2-Bromo-acetyl}-phenoxy)-acetic acid methyl ester (15 g; 52.3 mmol)in dry chloroform (300 ml) and the reaction mixture was stirredovernight. Dry ether (250 ml) was added and the white solid thatseparated was filtered, washed with CHCl₃-Ether 1:1 (2×30 ml), dried (22g), treated with MeOH (35 ml), conc.HCl (17.5 ml) and stirred overnightat room temperature. The reaction mixture was concentrated, filtered andthe solid obtained was washed with cold water (5 ml), ether, ethylacetate and dried to obtain the title compound of example 1e (5.2 g,39%). The filtrate was diluted with water (100 ml) and neutralised withNaHCO₃ at 0° C. A solution of (Boc)₂O (8.7 g) in dioxane (100 ml) wasadded and the mixture was stirred for 2 h, concentrated and extractedwith EtOAc. The organic layer was washed with water, brine, dried(Na₂SO₄) and concentrated to obtain the crude product, which washydrolysed with 1N methanolic NaOH for 1 h. The reaction mixture wasprocessed as is routinely done and crystallised using EtOAc-PE 60-80° C.to obtain the title compound of example 1f (8.1 g, 50%); mp, 51-53° C.;MS (ESI⁺): 332 (M⁺+Na⁺) 310 (M⁺+1), (ER) 308 (M⁺-1).

Example 1g(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester

NaHCO₃ (4.6 g; 54.8 mmol) was added with stirring to a solution of thecompound of example 1e (5 g; 16.44 mmol) in dry DMF (50 ml) at −25° C.Subsequently compound of example 1d (3.673 g; 13.7 mmol) indichloromethane (50 ml) was added drop wise over a period of 1 h. Thereaction mixture was maintained at −25° C. for an additional 30 min.,gradually brought to room temperature and stirred overnight. It wasdiluted with water and extracted with EtOAc (3×30 ml). The combinedorganic layers was washed with water, dilute aqueous HCl, brine, dried(Na₂SO₄), concentrated and purified using flash chromatography (silicagel, 5-10% CH₃CN in CHCl₃) to obtain the title compound. Yield, 1.5 g(30.12%); mp, 185-187° C.; MS (EI): 364 (M⁺), 193 (100%), 171, 116;analysis: C₂₀H₁₆N₂O₅ requires, C, 65.93; H, 4.43; N, 7.69. found, C,65.64; H, 4.44; N, 7.22%.

Example 1h(4-{2-[1-Oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)aceticacid methyl ester

H₂S gas was passed through a solution of the compound of example 1g (0.6g, 1.65 mmol) in pyridine/Et₃N::5/1(50 ml) for 30 min. to obtain anamber coloured solution which was stirred at room temperature till thestarting material was consumed. It was concentrated and purified usingflash chromatography (silica gel, 3% MeOH in CHCl₃) to obtain the titlecompound as a pale yellow solid. Yield, 0.628 g (95.73%); ¹H-NMR(DMSO-D₆): 3.72 (3H, s, OCH ₃), 4.56, 4.98, 5.13 (6H, 3×s, 3×CH ₂), 7.12(2H, d, J=8.7, H-2′ & H-5′), 7.75 (1H, d, J=7.75, H-7), 7.96 (1H, dd,J=7.75, 2.0, H-6), 8.10 (1H, d, J=2.0, H-4), 8.05 (2H, d, J=8.72, H-3′ &H-5′), 9.70, 10.10 (2H, 2×s, NH ₂).

Example 1i(4-{2-[5-Methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester, hydro iodide

A solution of the compound of example 1h (0.628 g; 15.78 mmol) andiodomethane (1 ml) in dry acetone (45 ml) was refluxed for 3 h. It wasconcentrated to obtain the title compound as a yellow solid. Yield, 0.8g (93.89%); ¹H-NMR (DMSO-D₆): 2.84 (3H, s, SCH ₃), 3.72 (3H, s, OCH ₃),4.64, 4.98. 5.17 (6H, 3×s, 3×CH ₂), 7.12 (2H, d, J=9.15, H-2′ & H-6′),7.98 (2H, m, H-6 & H-7), 8.04 (2H, d, J=9.15, H-3′ & H-5′), 8.15 (1H,br, H-4).

Example 2(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester, hemihydrate

A mixture of the compound of example 1g (0.3 g; 0.824 mmol),hydroxylamine hydrochloride (0.22 g; 3.3 mmol) and NaHCO₃ (0.3 g; 3.3mmol) in MeOH (25 ml) was stirred at room temperature for 3 h. It wasconcentrated, purified using flash chromatography (silica gel, 5-10%MeOH+1% AcOH in CHCl₃) and crystallized from MeOH-ether to obtain thetitle compound. Yield, 0.135 g (40.3%); mp, 175-176° C.; analysis:C₂₀H₁₉N₃O₆, 0.5 H₂O requires, C, 59.19; H, 4.96; N, 10.33. found: C,58.32; H, 4.72; N, 10.12%.

Example 3(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 3d usingthe procedure described in Example 1. The crude product was purifiedusing flash chromatography (RP-18, MeOH: 0.2% AcOH (1:1)) andcrystallized from dry MeOH-ether. Yield, 44%; mp, 185-87° C.; MS (ESI⁺):396 (M⁺+1); analysis: C₂₃H₂₅N₃O₇ requires: C, 60.65; H, 5.53; N, 9.23.found: C, 60.27; H, 5.49; N, 9.20%.

Example 3a (4-{2-Amino-acetyl}-phenoxy)-acetic acid ethyl ester,hydrochloride

The title compound was obtained from (4-{2-Bromo-acetyl}-phenoxy)-aceticacid ethyl ester (9.03 g; 30 mmol) using the procedure described inexample 1e and example 1f. Yield, 2.9 g (35.5%); ¹H-NMR (CDCl₃): 1.33(3H, t, J=7.3, CH₂CH₃), 4.30 (2H, q, J=7.3, CH₂CH₃), 4.60, 4.83 (4H,2×s, 2×CH ₂), 7.15 (2H, d, J=8.7, H-3 & H-5), 8.08 (2H, d, J=8.7, H-2 &H-6). Compound of example 1f was also obtained. Yield, 4.17 g (45%)

Example 3b(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)aceticacid ethyl ester

The title compound was obtained from the compound of example 3a usingthe procedure described in example 1g. Yield, 1.47 g (51%); mp, 186-87°C. (CHCl₃-PE 60-80° C.); MS (ESI): 377 (M−1).

Example 3c(4-{2-[1-Oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 3b usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN+0.5% MeOH in CHCl₃).Yield, 81%; mp, 185-186° C.; MS (ESI⁻): 411 (M−1), analysis: C₂₁H₂₀N₂O₅Srequires, C, 61.17; H, 4.85; N, 6.80, S, 7.77. found: C, 61.24; H, 4.68;N, 6.68; S, 8.09%.

Example 3d(4-{2-[5-Methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 3c usingthe procedure described in example 1i. Yield, 85.8%; mp, 180-183° C.; MS(ESI⁺): 449 (M⁺+Na⁺); analysis: C₂₂H₂₄IN₂O₅S requires C, 47.65; H, 4.15;N, 5.05; S, 5.78. found: C, 48.06; H, 4.02; N, 4.73; S, 5.40%.

Example 4(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hemihydrate

Hydroxylamine hydrochloride (0.05 g; 0.75 mmol) was added to a solutionof the compound of example 3d (0.277 g; 0.5 mmol) in ethanol (10 ml),followed by the addition of NaHCO₃ (0.063 g; 0.75 mmol). The reactionmixture was stirred at room temperature for 1 h, concentrated andpurified using flash chromatography (silica gel, 3% MeOH in chloroform).Yield, 60%; mp, 175-78° C.; MS (ESI): 412 (M⁺+1); analysis C₂₁H₂₁N₃O₆,0.5 H₂O requires C, 59.96; H, 5.23; N, 10.0. found: C, 60.34, H, 5.16;N, 9.64%.

Example 5(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester, hemihydrate

The title compound was obtained from the compound of example 5e usingthe procedure described in example 1 (propane-2-ol was used instead ofmethanol). Yield, 46%, mp, 162° C.; MS (ESI⁺): 410 (M⁺+1); analysis:C₂₄H₂₇N₃O₇, 0.5H₂O requires C, 60.23; H, 5.90; N, 8.76. found: C, 59.92;H, 5.62; N, 8.61%.

Example 5a (4-{2-tert-Butoxycarbonylamino-acetyl}-phenoxy)-acetic acidisopropyl ester

A solution of DCC (2.06 g; 10 mmol) in EtOAc (10 ml) was added withstirring, at 0° C. to a mixture of the compound of example 1f (2.78 g; 9mmol) and propane-2-ol (2 ml) in EtOAc (20 ml). DMAP (1.1 g; 9 mmol) wasadded after 10 min and stirring continued for 2 h at 0° C. The reactionmixture was stored in a freezer overnight. The precipitated DCU wasfiltered and the filtrate was washed with brine, dried (Na₂SO₄),concentrated and purified using flash chromatography (silica gel, 5%CH₃CN in CHCl₃) to obtain the title compound. Yield, 3.0 g (94.9%); mp,62-64° C. (EtOAc-PE 60-80° C.); analysis: C₁₈H₂₅NO₆ requires C, 61.53;H, 7.17; N, 3.99. found: C, 61.94; H, 7.19; N, 3.95%.

Example 5b (4-{2-Amino-acetyl}-phenoxy)-acetic acid isopropyl ester,hydrochloride

A mixture of the compound of example 5a (2.5 g; 7.12 mmol), formic acid(12 ml) and anisole (0.4 ml) was stirred at room temperature for 4 h.Ethereal HCl (1 ml) was added and the reaction mixture was well stirred.It was concentrated, triturated with dry ether, decanted free of etherand thoroughly dried to obtain the title compound. Yield, 1.88 g(91.8%); ¹H NMR (D₂O): 1.24 [6H, d, J=7.0, CH(CH ₃)₂], 4.61 (2H, s, NHCH₂), 4.86 (2H, s, OCH ₂CO), 5.08 (1H, hep, J=7.0, CHMe₂), 7.05, 7.94 (4H,2×d, J=8.1, ArH).

Example 5c(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester

The title compound was obtained from the compound of example 5b usingthe procedure described in example 1g. It was purified using flashchromatography (silica gel, 5% CH₃CN—CHCl₃). Yield, 30%; mp, 147-49° C.;analysis: C₂₂H₂₀N₂O₅, 0.25H₂O requires C, 66.51; H, 5.03; N, 7.05.found: C, 66.94; H, 5.14; N, 7.14%.

Example 5d(4-{2-[1-Oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester

The title compound was obtained from the compound of example 5c usingthe procedure described in example 1h. Yield, 96.77%; mp, 165° C.; MS(ESI): 425 (M−1); analysis: C₂₂H₂₂N₂O₅S requires C, 61.96; H, 5.29; N,6.57. found: C, 62.37; H, 5.39; N, 6.50%.

Example 5e(4-{2-[5-Methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester, hydroiodide

The title compound was obtained from the compound of example 5d usingthe procedure described in Example 1i. Yield, 79%; mp, 190 (d); MS(ESI⁺): 463 (M⁺+Na).

Example 6(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester

Methyl chloroformate (0.023 ml; 0.29 mmol) was added with stirring at 0°C. to a mixture of the compound of example 5 (0.114 g; 0.28 mmol), 0.1Naqueous NaOH (2.80 ml; 0.28 mmol) and NaHCO₃ (0.024 g; 0.28 mmol) inwater (3 ml) and dioxan (6 ml). After 1 h, the reaction mixture wasextracted with EtOAc. The organic layer was washed with brine, dried(Na₂SO₄), concentrated and purified using flash chromatography (silicagel, 3% MeOH—CHCl₃). Crystallization was carried out using EtOAc-PE60-80° C. to obtain the title compound. Yield, 0.12 g (94.2%); mp,183-84° C.; MS (ESI⁺): 490 (M⁺+Na⁺), 468 (M⁺+1); analysis: C₂₄H₂₅N₃O₇requires C, 61.66; H, 5.39; N, 8.99. found: C, 61.20; H, 5.23; N, 8.83%.

Example 7(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester, hemihydrate

The title compound was obtained from the compound of example 5 using theprocedure described in example 6 Isobutyl chloroformate was used insteadof methyl chloroformate. Yield, 40%; mp, 155-57° C.; MS (ESI⁺): 532(M⁺+Na⁺), 510 (M⁺+1); analysis: C₂₇H₃₁N₃O₇, 0.5H₂O requires, C, 62.48;H, 6.17; N, 8.11. found, C, 62.62; H, 6.09; N, 7.95%.

Example 8(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid isopropyl ester, hemihydrate

The title compound was obtained from the compound of example 5 using theprocedure described in example 6. Benzyl chloroformate was used insteadof methyl chloroformate. Yield, 56%; mp, 156-58° C.; MS (ESI⁺): 566(M⁺+Na⁺), 544 (M⁺+1); analysis: C₃₀H₂₉N₃O₇, 0.5H₂O requires C, 65.22; H,5.48; N, 7.60. found, C, 65.56; H, 5.42; N, 7.58%.

Example 9(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester, hemihydrate

The title compound was obtained from the compound of example 5e usingthe procedure described in example 4. Propane-2-ol was used instead ofethanol. Yield, 75.3%; mp, 164-66° C.; MS (ESI⁺): 448 (M⁺+Na⁺), 426(M⁺+1); analysis: C₂₂H₂₅N₃O₅, H₂O requires C, 61.50; H, 5.82; N, 9.79.found, C, 61.70; H, 5.39; N, 10.06%.

Example 10(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester, hydroiodide

The title compound was obtained from the compound of example 10e usingthe procedure described in example 1. Isobutanol was used instead ofmethanol. Yield, 46%; mp, 105° C.; MS (CI): 435 (M⁺+29), 407 (M⁺+1);analysis: C₂₃H₂₆N₃O₅I, requires C, 50.10; H, 4.75; N, 7.62; I, 23.01.found: C, 50.11; H, 5.06; N, 7.28; I, 22.78%.

Example 10a (4-{2-[tert-Butoxycarbonylamino]-acetyl}-phenoxy)-aceticacid isobutyl ester

The title compound was obtained from the compound of example 1f usingthe procedure described in example 5a. 2-methyl-1-propanol was usedinstead of propane-2-ol. Yield, 93.44%; oil; MS (ESI⁺): 388 (M⁺+Na), 366(M⁺+1), ¹H NMR (CDCl₃): 0.91 (6H, d, J=7.1, CH(CH ₃)₂], 1.49 [9H, s, (CH₃)₃], 1.96 (1H, m, CHMe₂), 4.0 (2H, d, J=7.6, CH ₂CHMe₂), 4.56 (2H, d,J=5.5, NHCH ₂), 4.73 (2H, s, OCH ₂CO), 5.57 (1H, br, NH), 6.96 (2H, d,J=8.2, H-2 & H-6), 7.96 (2H, d, J=8.2, H-3 & H-5).

Example 10b (4-{2-Amino-acetyl}-phenoxy)-acetic acid isobutyl ester,hydrochloride

The title compound was obtained from the compound of example 10a usingthe procedure described in example 5b. Yield, 89%.

Example 10c(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester

The title compound was obtained from the compound of example 10b usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN—CHCl₃). Yield, 25%; mp,144-45° C.; MS (ESI⁺): 429 (M⁺+Na); analysis: C₂₃H₂₂N₂O₅, H₂O requiresC, 65.02; H, 5.65; N, 6.59. found: C, 65.45; H, 5.32; N, 6.51%.

Example 10d(4-{2-[1-Oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester

The title compound was obtained from the compound of example 10c usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 1% MeOH in CHCl₃). Yield, 95.7%;MS (ESI⁻): 439 (M−1); analysis: C₂₃H₂₄N₂O₅S, requires C, 62.71; H, 5.49;N, 6.36. found: C, 62.90; H, 5.72; N, 6.45%.

Example 10e(4-{2-[5-Methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester, hydroiodide

The title compound was obtained from the compound of example 10d usingthe procedure described in example 11 in 73% yield. MS (ESI: 478(M⁺+Na), 456 (M⁺+1); ¹H NMR (DMSO-D₆): 0.87 [6H, d, J=7.03, CH(CH ₃)₂],1.96 [1H, m, CH₂CH(CH₃)₂], 2.85 (3H, s, SCH ₃), 3.94 (2H, d, J=6.4, CH₂CH(CH₃)₂], 4.64, 4.99, 5.17 (6H, 3×s, 3×CH ₂), 7.14 (2H, d, J=8.3, H-2′& H-6′), 7.98 (2H, br, H-6, H-7), 8.05 (2H, d, J=8.5, H-3′, H-5′), 8.16(1H, br, H-4).

Example 11(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester

The title compound was obtained from the compound of example 10 usingthe procedure described in example 6. The crude product was purifiedusing flash chromatography (silica gel with 3% MeOH—CHCl₃).Crystallization was carried out using hot EtOAc-PE60-80° C. Yield, 42%;mp, 162-63° C.; MS (ESI⁺): 504 (M⁺+Na⁺), 482 (M⁺+1); analysis:C₂₅H₂₇N₃O₇ requires C, 62.36; H, 5.65; N, 8.73. found: C, 62.41; H,5.77; N, 9.08%.

Example 12(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester, sesquihydrate

The title compound was obtained from the compound of example 10 usingthe procedure described in example 6 Isobutyl chloroformate was usedinstead of methyl chloroformate. The crude product was purified usingflash chromatography (silica gel, ether/dichloromethane [1:1]) andcrystallised using CHCl₃-PE60-80° C. Yield, 59%; mp, 140-41° C.; MS(ESI⁺): 546 (M⁺+Na⁺), 524 (M⁺+1); analysis: C₂₈H₃₃N₃O₇, requires C,61.03; H, 6.54; N, 7.63. found, C, 61.16; H, 6.35; N, 7.49%.

Example 13(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester

The title compound was obtained from the compound of example 10 usingthe procedure described in example 6. Benzyl chloroformate was usedinstead of methyl chloroformate. Yield, 50%; mp, 139-40° C. (CHCl₃-PE60-80° C.); MS (ESL): 580 (M⁺+Na⁺), 558 (M⁺+1); analysis: C₃₁H₃₁N₃O₇,requires C, 66.78; H, 5.60; N, 7.54. found, C, 66.44; H, 5.58; N, 7.22%.

Example 14(4-{2-[5-(Imino-methanesulfonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid isobutyl ester

Aqueous 0.1 N NaOH (2.7 ml; 0.27 mmol) was added with stirring over aperiod of 10 min. to an aqueous solution of the compound of example 10(0.138 g; 0.25 mmol, 4 ml) chilled in an ice bath at 0° C. The reactionmixture was extracted with dichloromethane and dried (Na₂SO₄). Thedichloromethane layer (10 ml) was decanted, cooled to 0° C., treatedwith NaHCO₃ (0.06 g; 0.7 mmol) and subsequently with freshly distilledmethanesulfonyl chloride (0.05 ml; 0.64 mmol) under vigorous stirringconditions which was continued for 30 min at 0° C. and for 2 h at roomtemperature. The reaction mixture was concentrated and the residue waspurified using flash chromatography (silica gel, 2.5% MeOH inchloroform). Crystallisation was carried out using 5% MeOH—CHCl₃ and dryether. Yield, 0.05 g (40%); mp, 177-78° C.; MS (ESI⁺): 524 (M⁺+Na⁺), 502(M⁺+1); analysis: C₂₄H₂₇N₃O₇S, requires C, 57.47; H, 5.43; N, 8.38, S,6.39. found, C, 57.88; H, 5.50; N, 8.32; S, 6.78%.

Example 15(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester

The title compound was obtained from the compound of example 10e usingthe procedure described in example 4. Isobutanol was used instead ofEtOH. The crude product was purified using flash chromatography (silicagel, 2.5% MeOH in chloroform). Yield, 74.3%; mp, 153-54° C.; MS (ESI⁺):462 (M⁺+Na⁺), 440 (M⁺+1); analysis: C₂₃H₂₅N₃O₆, requires C, 62.86; H,5.73; N, 9.56. found, C, 62.58; H, 5.61; N, 9.29%.

Example 16(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester, acetic acid salt, monohydrate

The title compound was obtained from the compound of example 16e usingthe procedure described in example 1. Isobutanol was used instead ofmethanol. Yield, 38%; mp, 190° C. (d); MS (ESI⁺): 480 (M⁺+Na), 458(M⁺+1); analysis: C₂₈H₂₇N₃O₇, H₂O requires C, 63.81; H, 5.57; N, 7.97.found: C, 63.59; H, 5.28; N, 7.70%.

Example 16a (4-{2-[tert-Butoxycarbonylamino]-acetyl}-phenoxy)acetic acidbenzyl ester

A solution of hexamine (7.1 g; 50.7 mmol) in chloroform (100 ml) wasadded to (4-{2-bromo-acetyl}-phenoxy)-acetic acid benzyl ester (18.2 g;50.13 mmol) with stirring at room temperature over a period of 1 h. Dryether (100 ml) was added and the solid hexamine salt obtained wasfiltered, dried (19 g; 37.77 mmol) and hydrolysed with 1.5N HCl (300 ml)for 16 h. The mixture was concentrated to a volume of 100 ml, cooled to0° C. and neutralized with NaHCO₃. A solution ofdi-tert-butyldicarbonate (12 g; 55 mmol) in dioxane (100 ml) was addedwith stirring and the reaction mixture was allowed to stir, at 0° C. for1 h and subsequently at room temperature for 1 h. It was concentratedand extracted with EtOAc. The EtOAc layer was washed with brine, dried(Na₂SO₄), concentrated and purified using flash chromatography (silicagel) to obtain the title compound. Yield, 5.4 g (27%); MS (CI): 400(M⁺+1), 344, 300, 196, 152; ¹H NMR (CDCl₃): 1.49 [9H, s, (CH ₃)₃], 4.61(2H, d, J=5.5, NHCH ₂), 4.76 (2H, s, OCH ₂CO), 5.26 (2H, s, CH ₂Ph) 5.57(1H, br, NH), 6.94, 7.90 (4H, 2×d, J=8.02, ArH), 7.32-7.40 (5H, br,CH₂PhH).

The acid compound of example 1f was obtained in 58% yield.

Example 16b (4-{2-Amino-acetyl}-phenoxy)-acetic acid benzyl ester,hydrochloride

The title compound was obtained from the compound of example 16a usingthe procedure described in example 5b. Yield, 78%; MS (ESI: 300 (M⁺+1);¹H NMR (DMSO-D₆): 4.51, 5.05, 5.21 (6H, 3×s, 3×CH ₂), 7.12, 7.97 (4H,2×d, J=8.01, Ar—H), 7.38 (5H, m, CH₂PhH).

Example 16c(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester

The title compound was obtained from the compound of example 16b usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN—CHCl₃). Yield, 25.4%;mp, 159-60° C.; MS (ESI⁺): 463 (M⁺+Na); analysis: C₂₆H₂₀N₂O₅ requires C,70.90; H, 4.58; N, 6.36. found: C, 70.61; H, 4.49; N, 5.98%.

Example 16d(4-{2-[1-Oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester

The title compound was obtained from the compound of example 16c usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 1% MeOH in CHCl₃). Yield, 93%;mp, 137-38° C.; MS (ESI⁺): 473 (M−1); analysis: C₂₆H₂₂N₂O₅S, H₂Orequires C, 64.75; H, 4.62; N, 5.62. found: C, 64.52; H, 4.96; N, 5.79%

Example 16e(4-{2-[5-Methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester, hydroiodide

The title compound was obtained from the compound of example 16d usingthe procedure described in example 11. Yield, 84.2%; ¹H NMR (DMSO-D₆):2.84 (3H, s, SCH ₃), 4.64, 5.05, 5.17, 5.23 (8H, 4×s, 4×CH₂), 7.13 (2H,d, J=8.7, H-2′& H-6′), 7.39 (5H, br, PhH), 7.98 (2H, br, H-6, H-7), 8.04(2H, d, J=8.7, H-3′, H-5′), 8.25 (1H, br, H-4).

Example 17(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid hydrochloride, monohydrate

The compound of example 16 (0.1 g) was dissolved in glacial acetic acid(30 ml) at 80° C. and the hot solution was hydrogenated using 10% Pd—C(0.01 g) for 40 min. The catalyst was filtered off and the filtrate wasconcentrated to obtain the title compound, which was purified usingflash chromatography (RP-18, MeOH-1% AcOH [1:1]). Yield, 0.03 g; mp,302° C.; MS: 390 (M⁺+Na), 368 (M⁺+1); ¹H NMR (TFA): 2.2 (3H, s), 4.77,4.85, 5.32 (6H, 3×s, 3×CH ₂), 7.05 (2H, d, J=8.02), 8.1 (5H, m).

Alternative Method:

The crude compound of example 17 (b) (0.12 g) was dissolved in a mixtureof formic acid (3 ml) and anisole (0.13 ml). The clear solution was keptat room temperature for 4 h. It was stirred with ethereal HCl (0.5 ml)for 2 min., evaporated to dryness and treated with dry ether. The solidobtained was filtered and washed with dry ether. Purification waseffected by trituration with MeOH, filtration and drying to obtain thetitle compound of as a white solid. Yield, 0.04 g; mp>250° C. (d); MS(ESI⁺): 368 (M⁺+1); analysis: C₁₉H₁₈ClN₃O₅, H₂O requires C, 56.05; H,4.74; N, 9.96; Cl, 8.42. found: C, 54.11; H, 4.66; N, 9.46; Cl, 8.41%.

Example 17a(4-{2-[5-(tert-Butoxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

Aqueous 0.1N NaOH (1.2 ml; 1.2 mmol) was added to a solution of thecompound of example 3 (0.6 g; 1.2 mmol) in dioxane (15 ml) and water (15ml) at 0° C., with stirring, followed by the addition of NaHCO₃ (0.11 g;1.2 mmol) and di-tert-butyl-dicarbonate (0.35 g; 1.44 mmol). Thereaction mixture was stirred at 0-10° C. for 3 h, concentrated, treatedwith water and extracted with EtOAc. The EtOAc layer was washed withwater, dried (Na₂SO₄), concentrated and purified using flashchromatography (silica gel, 20% CH₃CN in chloroform, 2% MeOH inchloroform). Yield, 0.51 g (78.3%); ¹H NMR (DMSO-D₆): 1.23 (3H, t,J=7.3, CH₂CH ₃), 1.48 [9H, s, C(CH ₃)₃], 4.17 (2H, q, J=7.3, CH ₂CH₃),4.57, 4.95, 5.14 (6H, 3×s, 3×CH ₂), 7.11 (2H, d, J=8.6, H-2′& H-6′),7.81 (1H, d, J=7.3, H-7), 8.05 (3H, m, H-6, H-3′, H-5′), 8.2 (1H, br,H-4), 9.1 (2H, br, 2×NH); MS (ESI⁺): 519 (M⁺+Na), 496 (M⁺+1).

Example 17b(4-{2-[5-(tert-Butoxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid

Aqueous 0.1N NaOH (11.4 ml; 1.14 mmol) was added to a solution of thecompound of example 17a (0.375 g; 0.756 mmol) in MeOH (10 ml), Thereaction mixture was stirred at room temperature for 30 min., acidifiedwith AcOH and concentrated. The crude title compound obtained wasfiltered, washed with cold water and dried under vacuum. Yield, 140 mg.

Example 18(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester, hemihydrate

The title compound was obtained from the compound of example 16 usingthe procedure described in example 6. The crude product was purifiedusing flash chromatography (silica gel, 3% MeOH—CHCl₃). Crystallizationwas carried out using hot EtOAc-PE 60-80° C. Yield, 40%; mp, 184-86° C.;MS (ESI⁺): 538 (M⁺+Na⁺), 516 (M⁺+1); analysis: C₂₈H₂₅N₃O₇, 0.5H₂Orequires C, 64.12; H, 4.96; N, 8.02. found: C, 64.36; H, 4.92; N, 8.18%.

Example 19(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester, monohydrate

The title compound was obtained from the compound of example 16 usingthe procedure described in example 6. Isobutyl chloroformate was usedinstead of methyl chloroformate. The crude product was purified usingflash chromatography (silica gel, 10% CH₃CN in CHCl₃). Crystallizationwas carried out using CHCl₃-PE 60-80° C. Yield, 29%; mp, 162-63° C.; MS(ESI⁺): 580 (M⁺+Na⁺), 558 (M⁺+1); analysis: C₃₁H₃₁N₃O₇, H₂O requires C,65.95; H, 5.65; N, 7.42. found, C, 65.94; H, 5.64; N, 7.59%.

Example 20(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethoxycarbonylmethoxy-phenoxy)-acetic acid ethyl ester; acetic acid salt, hydrate

The title compound was obtained from the compound of example 20i usingthe procedure described in example 1. Ethanol was used instead ofmethanol. mp, 168-69° C.; MS (ESI⁺): 520 (M⁺+Na); analysis: C₂₇H₃₁N₃O₁₀,H₂O requires C, 56.35; H, 5.74; N, 7.3. found: C, 56.29; H, 5.40; N,6.97%.

Example 20a (2-Ethoxycarbonylmethoxy-phenoxy)-acetic acid ethyl ester

Ethyl 2-bromoacetate (36.5 ml; 165 mmol) was added slowly with stirringat room temperature over a period of 1.5 to a mixture of catechol (16.5g; 150 mmol) and anhydrous K₂CO₃ (55 g) in dry DMF (150 ml). Thereaction mixture was poured over crushed ice and extracted with EtOAc.The EtOAc layer was washed with water, dried (Na₂SO₄), concentrated andpurified using flash chromatography (silica gel, 5% CH₃CN in chloroform)to obtain the title compound. Yield, 38.07 g (90%), oil; analysis:C₁₄H₁₈O₆ requires C, 59.57; H, 6.43. found: C, 59.48; H, 6.34%.

Example 20b (4-Acetyl-2-ethoxycarbonylmethoxy-phenoxy)-acetic acid ethylester

Perchloric acid (70% aq.; 1.0 ml) was added slowly to freshly distilledAc₂O (25 ml) at 0° C. The compound of example 20a (31.8 g; 125 mmol) inCH₂Cl₂ (13 ml) was added drop wise at 10-15° C. The reaction mixture washeated on steam bath for 1 h, concentrated, poured over crushed ice andNaHCO₃ (˜25 g) and extracted with ether. The ether layer was washed withbrine, dried (Na₂SO₄), concentrated and purified using flashchromatography (silica gel, 5% CH₃CN in CHCl₃) to obtain the titlecompound. Yield, 24.6 g (61.5%), semisolid; analysis: C₁₆H₂₀O₇: requiresC, 59.25; H, 6.22. found: C, 59.57; H, 6.28%.

Example 20c (4-{2-Bromo-acetyl}-2-ethoxycarbonylmethoxy-phenoxy)-aceticacid ethyl ester

Bromine (4.25 ml; 85 mmol) in AcOH: CHCl₃ (1:1; 10 ml) was added to avigorously stirred solution of the compound of example 20b (25.92 g; 80mmol) in AcOH:CHCl₃ (1:1; 110 ml) at 55-60° C. for 15 min. The mixturewas stirred at room temperature for 5 min. and poured over crushed iceand NaHCO₃ and extracted with EtOAc. The EtOAc layer was washed withwater, dried (Na₂SO₄), concentrated and purified using flashchromatography (silica gel, 3% CH₃CN in chloroform) to obtain the titlecompound. Yield, 19.34 g, (60%); mp, 84-85° C. (EtOAc-PE 60-80° C.);analysis: C₁₆H₁₉O₇Br: requires C, 47.66; H, 4.75; Br, 19.82. found: C,48.08; H, 4.82; Br, 19.40%.

Example 20d(4-{2-tert-Butoxycarbonylamino-acetyl}-2-ethoxycarbonylmethoxy-phenoxy)-aceticacid ethyl ester Example 20e(4-{2-tert-Butoxycarbonylamino-acetyl}-2-carboxymethoxy-phenoxy)-aceticacid

The compound of example 20d (oil) and the compound of example 20e wereobtained from the compound of example 20c using the procedure describedin example 16a. Yield, (40%); MS (ESI⁺): 462 (M⁺+Na); ¹H NMR (CDCl₃):1.30, (6H, m, 2×CH₂CH ₃), 1.46 [9H, s, C(CH ₃)₃], 4.26 (4H, q, J=7.3,2×CH ₂CH₃), 4.60 (2H, d, J=5.0, NHCH ₂), 4.77, 4.81 (4H, 2×s, 2×OCH₂),5.53 (1H, br, NH), 6.86 (1H, d, J=8.2, H-6), 7.50 (1H, d, J=1.8, H-3),7.57 (1H, dd, J=8.2, 1.8, H-5).

The acid compound of example 20e was obtained as a solid. Yield, (50%).

Example 20f (4-{2-Amino-acetyl}-2-ethoxycarbonylmethoxy-phenoxy)-aceticacid ethyl ester, hydrochloride

The title compound was obtained from the compound of example 20d usingthe procedure described in example 5b. Solvent of crystallization:MeOH-ether. Yield, 75%.

Example 20g(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethoxycarbonylmethoxy-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 20e usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN—CHCl₃). Yield, 22%; mp,120-21° C.; MS (ESI⁺): 503 (M⁺+Na); analysis: C₂₂H₂₀N₂O₅, 0.25H₂Orequires C, 66.51; H, 5.03; N, 7.05. found: C, 66.94; H, 5.14; N, 7.14%.

Example 20h(2-Ethoxycarbonylmethoxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 20g usingthe procedure described in example 1h. Yield, 75%; mp, 169-70° C.; MS(ESI⁺): 537 (M⁺+Na); analysis: C₂₅H₂₆N₂O₈S requires C, 58.36; H, 5.09;N, 5.44; S, 6.23. found: C, 58.52; H, 5.08; N, 5.11; S, 6.62%.

Example 20i(2-Ethoxycarbonylmethoxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 20h usingthe procedure described in example 11. Yield, 79%, yellow solid; mp,168-69° C.; MS (ESI⁺): 551 (M⁺+Na); analysis; C₂₆H₂₉N₂O₈SI requires C,47.56; H, 4.42; N, 4.27; S, 4.88; I, 19.36. found C, 47.72; H, 4.49; N,4.56; S, 4.69; I, 19.54%.

Example 21(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 20i usingthe procedure described in example 4. Yield, 52%; mp, 163-64° C.; MS(ESI⁺): 536 (M⁺+1); analysis: C₂₅H₂₇N₃O₉, requires C, 58.48; H, 5.30; N,8.18. found, C, 58.16; H, 5.19; N, 8.08%.

Example 22(2-Ethoxycarbonylmethoxy-4-{2-[5-(imino-{3-methyl-butyrylamino}-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 20 usingthe procedure described in example 6. Isobutyl chloroformate was usedinstead of methyl chloroformate. Yield, 24%. mp, 204-05° C.; MS (ESI:598 (W+1); analysis: C₃₀H₃₅N₃O₁₀, requires C, 60.29; H, 5.90; N, 7.03.found, C, 60.70; H, 6.28; N, 6.96%.

Example 23(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-1-hydroxyimino-ethyl}-phenoxy)-aceticacid ethyl ester

A mixture of the compound of example 20g (0.14 g; 0.3 mmol),hydroxylamine hydrochloride (0.07 g; 1.11 mmol) and Na₂CO₃ (0.053 g;0.51 mmol) in ethanol (0.5 ml) and water (1.5 ml) was refluxed in anatmosphere of nitrogen for 1 h. The reaction mixture was cooled to roomtemperature, concentrated and treated with water to obtain the titlecompound as a white solid which was filtered, washed with cold water anddried. Yield, 0.051 g (32.2%); mp, 181-82° C.; MS (ESI⁺): 551 (M⁺+Na⁺);analysis: C₂₅H₂₈N₄O₉, requires C, 56.81; H, 5.34; N, 10.60. found C,56.33; H, 5.25; N, 10.16%

Example 24(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isobutoxycarbonyl methoxy-phenoxy)acetic acid isobutyl ester, hydroiodide

The title compound was obtained from the compound of example 24e usingthe procedure described in example 1. Isobutanol was used instead ofmethanol. Yield, 10%; mp, 95-96° C.; MS (ESI⁺): 554 (M⁺+1); analysis:C₂₉H₃₆IN₃O₈, requires C, 51.11; H, 5.32; N, 6.17. found: C, 51.42; H,5.51; N, 6.05%.

Example 24a(4-{2-tert-Butoxycarbonylamino-acetyl}-2-isobutoxycarbonylmethoxy-phenoxy)-aceticacid isobutyl ester

The title compound (oil) was obtained from the compound of example 20eusing the procedure described in example 5a. Isobutanol was used insteadof propane-2-ol together with 2.2 equivalents of DCC. Yield, (54%);(CDCl₃): 0.91, 0.95 [12H, 2×d, J=8.5, 2×CH(CH ₃)₂], 1.46 (9H, s, C(CH₃)₃], 1.94 (2H, m, 2×CH₂CHM₂), 3.97 (4H, d, J=6.7, CH ₂CHMe₂), 4.56 (2H,d, J=4.5, NHCH ₂), 4.80, 4.83 (4H, 2×s, 2×OCH ₂), 5.51 (1H, br, NH),6.86 (1H, d, J=8.2, H-6), 7.50 (1H, d, J=2.0, H-3), 7.59 (1H, dd, J=8.2,2.0, H-5).

Example 24b(4-{2-Amino-acetyl}-2-isobutoxycarbonylmethoxy-phenoxy)-acetic acidisobutyl ester; hydrochloride

The title compound was obtained from the compound of example 24a usingthe procedure described in example 5b. Yield, 95%.

Example 24c(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isobutoxycarbonyl methoxy-phenoxy)-acetic acid isobutyl ester

The title compound was obtained from the compound of example 24b usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN—CHCl₃). Yield, 21%; mp,140-41° C.; MS (EI): 536 (M⁺); analysis: C₂₉H₃₂N₂O₈, requires C, 64.91;H, 6.01; N, 5.22. found: C, 65.15; H, 6.06; N, 4.95%.

Example 24d(2-Isobutoxycarbonylmethoxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester

The title compound was obtained from the compound of example 24c usingthe procedure described in example 1h. Yield, 68%; mp, 175-76° C.; MS(ESI⁺): 593 (M⁺+Na); analysis: C₂₉H₃₄N₂O₈S requires C, 61.04; H, 6.01;N, 4.91; S, 5.62. found: C, 60.84; H, 5.74; N, 4.87; S, 5.40%.

Example 24e(2-Isobutoxycarbonylmethoxy-4-{2-[5-methylsulfanylcarbonimidoyl-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester, hydroiodide

The title compound was obtained from the compound of example 24d usingthe procedure described in example 11. Yield, 87%, yellow solid; MS(ESI⁺): 608 (M⁺+Na).

Example 252-(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-N,N-diethyl-acetamide,acetic acid salt

The title compound was obtained from the compound of example 25e usingthe procedure described in example 1. Yield, 30%; mp, 194-95° C.; MS(ESI⁺): 423 (M⁺+1); analysis: C₂₅H₃₀N₄O₆ requires: C, 62.23; H, 6.27; N,11.61. found: C, 62.49; H, 6.18; N, 11.19%.

Example 25a (2-{4-Diethylcarbamoylmethoxy-phenyl}-2-oxo-ethyl)-carbamicacid tent-butyl ester

Isobutyl chloroformate (0.84 ml; 6.5 mmol) was added to a stirredsolution of 4-methyl-morpholine (0.72 ml; 6.5 mmol) and the compound ofexample 1f (2.0 g; 6.5 mmol) in DMF (10 ml) at −25° C., followed by theaddition of diethyl amine (0.88 ml; 8.45 mmol). The reaction mixture wasstirred for 15 min., poured into a 10% aqueous NaHCO₃ solution andextracted with EtOAc. The EtOAc layer was washed with brine,concentrated and crystallized using EtOAc-PE60-80° C. to obtain thetitle compound. Yield, 1.95 g (82%); mp, 100-01° C.; MS (EI): 364 (M⁺),291, 234 (100%); analysis: C₁₉H₂₈N₂O₅ requires C, 62.62; H, 7.74; N,7.69. found: C, 62.43; H, 7.60; N, 7.25%.

Example 25b 2-(4-{2-Amino-acetyl}-phenoxy)-N,N diethyl-acetamide,hydrochloride

The title compound was obtained from the compound of example 25a usingthe procedure described in example 5b. Yield, 95%; mp, 83-84° C.; MS(ESI): 265 (M⁺+1).

Example 25c2-(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-N,N-diethylacetamide

The title compound was obtained from the compound of example 25b usingthe procedure described in example 1g. Yield, 25%; mp, 139-40° C.; MS(EI): 405 (M⁺); analysis, C₂₃H₂₃N₃O₄ requires, C, 68.13; H, 5.72; N,10.36. found: C, 68.48; H, 5.86; N, 10.34%.

Example 25dN,N-Diethyl-2-(4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetamide

The title compound was obtained from the compound of example 25c usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN+0.5% MeOH in CHCl₃).Yield, 75%, yellow solid; mp, 191-192° C.; MS (ESI⁺): 462 (M⁺+Na),analysis: C₂₃H₂₅N₂O₄S requires C, 62.45; H, 5.73; N, 9.56, S, 7.29.found: C, 62.22; H, 5.59; N, 9.31; S, 7.01%.

Example 25e2-(2-{4-Diethylcarbamoylmethoxy-phenyl}-2-oxo-ethyl)-1-oxo-2,3-dihydro-1H-isoindol-5-carboximidothioicacid methyl ester, hydroiodide

The title compound was obtained from the compound of example 25d usingthe procedure described in example 11. Yield, 89%; MS (ESI): 452 (WA).

Example 264-(2-{4-[2-(5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylicacid benzyl ester, sesquihydrate

The title compound was obtained from the compound of example 26e usingthe procedure described in example 1. Propane-2-ol was used instead ofmethanol. Yield, 28%, white solid; mp, 180-81° C.; MS (ESI⁺): 585(M⁺+1); analysis: C₃₄H₃₆N₄O₉2.5H₂O requires: C, 59.21; H, 5.22; N, 8.12.found: C, 58.85; H, 5.23; N, 7.96.

Example 26a4-(2-{-4-[2-tert-Butoxycarbonylamino-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylicacid benzyl ester

The compound of example 1f was treated with4-hydroxy-piperidine-1-carboxylic acid benzyl ester in the presence ofDCC as described in the procedure of example 5a to obtain the titlecompound. The crude material was purified using flash chromatography(silica gel, 5% CH₃CN in chloroform). Yield, 73%; analysis: C₂₈H₃₄N₂O₈requires: C, 63.87; H, 6.51; N, 5.32. found: C, 64.13; H, 6.78; N,5.02%.

Example 26b4-(2-{-4-[2-Amino-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylic acidbenzyl ester, hydrochloride

The title compound was obtained from the compound of example 26a usingthe procedure described in example 5b. Yield, 80%.

Example 26c4-(2-{4-[2-(5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylicacid benzyl ester

The title compound was obtained from the compound of example 26b usingthe procedure described in example 1g. Yield, 20%; mp, 94-95° C.; MS(ESI⁻): 566 (M−1); analysis: C₃₂H₂₉N₃O₇ requires: C, 67.72; H, 5.15; N,7.40. found: C, 67.72; H, 5.25; N, 7.06%.

Example 26d4-(2-{4-[2-(1-Oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylicacid benzyl ester

The title compound was obtained from the compound of example 26c usingthe procedure described in example 1h. Yield, 57%; mp, 97-98° C.; MS(ESI⁺): 624 (M⁺+Na), 602 (M⁺+1); analysis: C₃₂H₃₁N₃O₇S requires: C,63.88; H, 5.19; N, 6.98; S, 5.33. found: C, 63.58; H, 5.14; N, 6.78; S,5.57%.

Example 26e4-(2-{4-[2-(5-Methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylicacid benzyl ester, hydroiodide

The title compound (yellow solid) was obtained from the compound ofexample 26d using the procedure described in example 11. Yield, 98%; MS(ESI⁺): 638 (M⁺+Na), 616 (M⁺+1); ¹H NMR (CDCl₃): 1.64, 1.89 (4H, 2×m),3.14 (3H, s, SCH ₃), 3.33, 3.67 (4H, 2×m), 4.68, 4.73, 5.05 (6H, 3×s,3×CH₂), 5.10-5.18 (3H, m, CH ₂& COOCH—), 6.99 (2H, d, J=8.6, H-2′ &H-6′), 7.36 (5H, br, CH₂PhH), 8.0 (4H, m, H-6, H-7, H-3′ & H-5′), 8.3(1H, s, H-4).

Example 274-Benzyloxycarbonylamino-2-(4-{2-[5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester, acetic acid salt

The title compound was obtained from the compound of example 27j usingthe procedure described in example 1. Ethanol was used instead ofmethanol. Yield, 38%, white solid; mp, 164-65° C.; MS (ESI⁺): 573(M⁺+1); analysis: C₃₃H₃₆N₄O₉ requires C, 62.36; H, 5.70; N, 8.86. found:C, 61.91; H, 5.68; N, 9.20%.

Example 27a 2-Amino-1-(4-benzyloxy-phenyl)-ethanone, hydrochloride

Hexamine (5.6 g; 40 mmol) was added to a solution of1-(4-benzyloxy-phenyl)-2-bromo-ethanone (12.2 g; 40 mmol) in chloroform(80 ml), and stirred for 3 h. Dry ether (80 ml) was added and the solidthat separated was filtered, washed with ether, dried then suspended inmethanol (100 ml) and con. HCl (20 ml) and allowed to stir for 16 h. Thereaction mixture was concentrated, and treated with water (20 ml). Thesolid obtained was filtered, washed with cold water (2×10 ml) and driedto obtain the title compound. Yield, 10 g (89.9%); mp, 228-29° C.; MS(EI): 241, 211, 91; analysis: C₁₅H₁₆ClNO₂ requires: C, 64.87; H, 5.81;N, 5.04. found: C, 64.86; H, 6.11; N, 5.16%.

Example 27b (2-{4-Benzyloxy-phenyl}-2-oxo-ethyl)-carbamic acidtert-butyl ester

The compound of example 27a (8.33 g; 30 mmol) was dissolved in water(100 ml) and dioxane (100 ml), cooled to 0° C. with stirring, andtreated with NaHCO₃ (5.2 g; 65 mmol) and (Boc)₂O (7.2 g; 33 mmol). Thereaction mixture was stirred at 0° C. for 1 h, subsequently at roomtemperature for 1 h and then concentrated. The residue was extractedwith EtOAc. The organic layer was washed with brine, dried (Na₂SO₄) andconcentrated to obtain the title compound which was then crystallizedfrom EtOAc-PE 60-80° C. Yield, 9.5 g (92.8%); mp 75-76° C.; MS (EI): 341(M⁺), 285, 268, 211, 91; analysis: C₂₀H₂₃1NO₄ requires: C, 70.36; H6.79; N, 4.10. found: C, 70.49; H, 7.22; N, 4.23%.

Example 27c (2-{4-hydroxy-phenyl}-2-oxo-ethyl)-carbamic acid tert-butylester

The compound of example 27b (6.0 g; 17.6 mmol) was dissolved in methanol(60 ml) and hydrogenated using 10% Pd—C (50 mg) at 40 psi for 2 h. Thereaction mixture was filtered, concentrated and purified using flashchromatography (silica gel, 3% CH₃CN in chloroform) to obtain the titlecompound. Yield, 2.6 g (59%); mp, 183-85° C.; MS (CI): 252 (M⁺+1), 196,178, 152; analysis: C₁₃H₁₇NO₄ requires: C, 62.14; H, 6.82; N, 5.57.found: C, 62.23; H, 6.44; N, 5.57%.

Another polar compound was also isolated and characterized as(2-Hydroxy-{2-[4-hydroxy-phenyl]}-ethyl)-carbamic acid tert-butyl ester.Yield, 1.5 g (25%); mp, 145-46° C.; analysis: C₁₃H₁₉NO₄ requires: C,61.64; H, 7.56; N, 5.53. found: C, 62.04; H, 7.91; N, 5.57%.

Example 27d 4-Benzyloxycarbonylamino-2S-hydroxy buyric acid ethyl ester

Freshly distilled thionyl chloride (5 ml) was added drop wise over aperiod of 15 min with stirring to a solution of4-Amino-2S-hydroxy-butyric acid (5 g, 42 mmol) in EtOH (100 ml) at 0° C.The reaction mixture was brought to room temperature and stirredovernight (16 h). It was concentrated under vacuum to remove all tracesof thionyl chloride, treated with water (100 ml), dichloromethane (50ml) and chilled to 0° C. NaHCO₃ (17.5 g) was added with stirring,followed by the addition of a solution of 50% benzyl chloroformate intoluene (14.3 ml). The reaction mixture was allowed to stir for 1 h at0° C. and subsequently at room temperature for 30 min. The organic layerwas separated, washed with brine, dried (Na₂SO₄), concentrated and.purified using flash chromatography (silica gel, 10% CH₃CN in CHCl₃) toobtain the title compound. Yield, 7.7 g (65.3%), oil; MS (EI): 281 (M⁺),238, 235, 208, 174; ¹H NMR (CDCl₃): 1.29 (3H, t, J=7.5, CH₂CH ₃), 1.86,2.06 [2H, 2×m, CH ₂CH(OH)], 3.18 (1H, d, J=6.40 OH), 3.4 (2H, m, NHCH₂), 4.22 (2H, q, J=7.7, CH ₂CH₃), 5.12 (2H, s, CH ₂Ph), 5.18 [1H, m,CH(OH)], 7.3-7.42 (5H, br, PhH).

Example 27e 4-Benzyloxycarbonylamino-2(S)-methanesulfonyloxy-butyricacid ethyl ester

Methanesulfonyl chloride (2.79 ml; 36 mmol) was added drop wise withstirring to a solution of the compound of example 27d (8.4 g; 30 mmol)in dichloromethane (90 ml) and pyridine (3.7 ml; 45.98 mmol) at 0° C.The reaction mixture was stirred at 0° C. for 2 h and subsequently atroom temperature overnight (16 h). It was processed as is routinely doneand was purified using flash chromatography (silica gel, 5% CH₃CN inchloroform). Yield, 6.6 g (61.3%); MS (CI): 360 (M⁺+1); ¹H NMR (CDCl₃):1.30 (3H, t, J=7.3, CH₂CH ₃), 2.28 (2H, 2×m, NHCH₂CH ₂), 3.18 (3H, s,SO₂CH ₃), 3.15, 3.35 (2H, 2×m, NHCH ₂), 4.25 (2H, q, J=7.3, CH ₂CH₃),5.1 (2H, s, CH ₂Ph), 5.18 [1H, m, CH(OSO₂Me)], 7.3-7.4 (5H, br, PhH).

Example 27f4-Benzyloxycarbonylamino-2(S)-(4-{2-tert-butoxycarbonylamino-acetyl}-phenoxy)-butyricacid ethyl ester

A mixture of compound of example 27c (4.0 g; 16 mmol), compound ofexample 27e (6.4 g; 18 mmol) and K₂CO₃ (4.5 g) in DMF (30 ml) wasstirred at 65° C. for 2.5 h. The reaction mixture was brought to roomtemperature and acidified with 2N HCl (20 ml). It was processed as isroutinely done and was purified using flash chromatography (silica gel,8% CH₃CN in chloroform). Yield, 5.6 g (68%), oil; ¹H NMR (CDCl₃): 1.23(3H, t, J=7.6, CH₂CH ₃), 1.5 [9H, s, C (CH ₃)₃], 2.25 (2H, m, NHCH₂CH₂), 3.45 (2H, 2×m, NHCH ₂CH₂), 4.22 (2H, q, J=7.6, CH ₂CH₃), 4.58 (2H,d, J=5.5, NHCH ₂), 4.80 (1H, t, J=5.5 NHCH₂CH₂), 5.1 (2H, s, CH ₂Ph),5.55 (1H, br, NHCH₂CO), 6.89 (2H, d, J=8.0, H-3 & H-5), 7.3-7.4 (5H, br,PhH). 7.92 (2H, d, J=8.0H-2 & H-6).

Example 27g2-(4-{2-Amino-acetyl}-phenoxy)-4-benzyloxycarbonylamino-butyric acidethyl ester, hydrochloride

The title compound was obtained from the compound of example 27f usingthe procedure described in example 5b. Yield, 90%; ¹H NMR (CD₃OD): 1.28(3H, t, J=7.3, CH₂CH ₃), 2.22 (2H, m, NHCH₂CH ₂), 3.40 (2H, 2×m, NHCH₂CH₂), 4.25 (2H, q, J=7.3, CH ₂CH₃), 4.58 (2H, d, J=5.5, NHCH ₂), 5.03(1H, m, —CHCOO), 5.10 (2H, s, CH ₂Ph), 7.08 (2H, d, J=9.0, H-3 & H-5),7.3-7.8 (5H, br, PhH), 8.05 (2H, d, J=8.0, H-2 & H-6).

Example 27h4-Benzyloxycarbonylamino-2-(4-{2-[5-cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester

The title compound was obtained from the compound of example 27g usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN in chloroform). Yield,12%; mp, 152-54° C. (CHCl₃-PE 60-80° C.); analysis: C₃₁H₂₉N₃O₇ requiresC, 67.03; H, 5.22; N, 7.57. found C, 66.83; H, 5.24; N, 7.52%.

Example 27i4-Benzyloxycarbonylamino-2-{4-[2-(1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-butyricacid ethyl ester

The title compound was obtained from the compound of example 27h usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN, 2% MeOH inchloroform). Yield, 93%; mp, 80-81° C.: MS (ESI⁻): 588 (M−1); ¹H NMR(CDCl₃): 1.25 (3H, t, J=8.8, CH₂CH ₃), 2.24 (2H, m, NHCH₂CH ₂), 3.44(2H, 2×m, NHCH ₂CH₂), 4.22 (2H, q, J=8.8, CH ₂CH₃), 4.58, 5.02, 5.18(6H, 3×s, 3×CH ₂), 4.80 (1H, t, NHCH₂), 5.04 (1H, m, —CHCOO), 6.94 (2H,d, J=8.8, H-2′& H-6′), 7.35 (5H, br, PhH), 7.50 (1H, br, CSNH ₂),7.75-7.78 (3H, m, CSNH ₂, H-6 & H-7), 7.95 (2H, m, H-3′ & H-5′), 8.01(1H, br, H-4).

Example 27j4-Benzyloxycarbonylamino-2-(4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 27i usingthe procedure described in example 11. Yield, 95%.

Example 284-Benzyloxycarbonylamino-2-(4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester

The title compound was obtained from the compound of example 27j usingthe procedure described in example 4. Purification was effected usingflash chromatography (silica gel, 3% MeOH in chloroform). Yield, 75%;mp, 174-75° C.; MS (ESI): 611 (M⁺+Na), 589 (M⁺+1); analysis: C₃₁H₃₂N₄O₈requires C, 63.26; H, 5.44; N, 9.52. found: C, 62.78; H, 5.28; N, 9.25%.

Example 29(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenylsulfanyl)-aceticacid methyl ester

The title compound was obtained from the compound of example 29g usingthe procedure described in example 4. Purification was effected usingflash chromatography (silica gel, 3% MeOH in chloroform). Yield, 24%(white solid); mp, 193-94° C.; MS (ESI⁺): 435 (M⁺+Na), 414 (M⁺+1);analysis: C₂₀H₁₉N₃O₅ requires C, 58.10; H, 4.63; N, 10.16; S, 7.75.found: C, 58.50; H, 4.67; N, 10.22; S, 7.66%.

Example 29a (4-Acetyl-phenylsulfanyl)-acetic acid methyl ester

A mixture of 1-(4-bromo-phenyl)-ethanone (40 g, 201 mmol),methyloxycarbonyl methanthiolate copper (I) (40.68 g; 241 mmol),quinoline (173 ml) and pyridine (13.6 ml) was heated at 180° C. for 2 h.The reaction mixture was poured over crushed ice, acidified with conc.HCl and extracted with EtOAc. The EtOAc layer was washed with water,brine, dried (Na₂SO₄), concentrated and purified using flashchromatography (silica gel, 20% EtOAc-PE 60-80° C.) to obtain the titlecompound. Yield, 20 g (44%), oil; MS (EI): 224 (M), 209; analysis:C₁₁H₁₂O₃S, 0.5H₂O requires C, 56.65; H, 5.57. found: C, 57.10; H, 5.35%.

Example 29b (4-{2-Bromo-acetyl}-phenylsulfanyl)-acetic acid methyl ester

The title compound was obtained from the compound of example 29a usingthe procedure described in example 20c. Yield, 82%; mp, 113-14° C.; MS(EI): (302,304) (M⁺), 209; analysis: C₁₁H₁₁BrO₃S requires C, 43.56; H,3.63; S, 10.56; Br, 26.40. found: C, 43.48; H, 3.67; S, 10.82; Br,27.82%.

Example 29c(4-{2-tert-Butoxycarbonylamino-acetyl}-phenylsulfanyl)-acetic acidmethyl ester

The title compound was obtained from the compound of example 29b usingthe procedure described in example 27a-b. Yield, 44%, light yellow gum;MS (ESI⁺): 362 (M⁺+Na), 340 (M⁺+1); analysis: C₁₆H₂₁NO₅S requires C,56.62; H, 6.24; N, 4.13; S, 9.45. found: C, 56.40; H, 6.28; N, 4.44; S,9.88%.

Example 29d (4-{2-Amino-acetyl}-phenylsulfanyl)-acetic acid methylester, hydrochloride

The title compound was obtained from the compound of example 29c usingthe procedure described in example 5b. Yield 93%; IR (KBr): 3365, 3000,1760, 1690, 1600; MS (ESI⁺): 240 (M⁺+1).

Example 29e(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenylsulfanyl)-aceticacid methyl ester

The title compound was obtained from the compound of example 29d usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 3-10% CH₃CN in chloroform).Yield, 17%; mp, 206-07° C.; MS (ESI⁺): 403 (M⁺+Na), 381 (M⁺+1);analysis: C₂₀H₁₆N₂O₄S requires C, 63.15; H, 4.24; N, 7.36; S, 8.43.found: C, 63.07; H, 4.18; N, 7.36; S, 8.84%.

Example 29f(4-{2-[1-Oxo-5-thiocarbamoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenylsulfanyl)-aceticacid methyl ester

The title compound was obtained from the compound of example 29e usingthe procedure described in example 1h. Yield, 70%; mp, 214-15° C.; MS(ESI): 413 (M−1); analysis: C₂H₁₈N₂O₄S requires C, 57.96; H, 4.38; N,6.76, S, 15.47. found: C, 58.14; H, 4.22; N, 6.67; S, 15.61%.

Example 29g(4-{2-[5-Methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenylsulfanyl)-aceticacid methyl ester, hydroiodide

The title compound was obtained from the compound of example 29f usingthe procedure described in example 11. Yield, 85%, yellow solid.

Example 30(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-chloro-phenoxy)-aceticacid ethyl ester, acetic acid salt

The title compound was obtained from the compound of example 30h usingthe procedure described in example 1. Yield, 43%, white solid; mp,172-73° C.; MS (ESI⁺): 452 (M⁺+Na), 430 (M⁺+1); analysis: C₂₃H₂₄ClN₃O₇,0.5H₂O; requires C, 55.37; H, 5.01; N, 8.42; Cl, 7.1.1. found, C, 55.38;H, 4.88; N, 8.18; Cl, 7.46%.

Example 30a (2-Chloro-phenoxy)-acetic acid ethyl ester

The title compound was prepared by reacting 2-chloro-phenol, with ethyl2-bromoacetate and K₂CO₃ in DMF. Yield, 97%, colourless oil; ¹H NMR(CDCl₃): 1.29 (3H, t, J=6.3, CH₂CH ₃), 4.29 (2H, q, J=6.3, CH ₂CH₃),4.72 (2H, s, OCH ₂), 6.76 (1H, d, J=8.2, H-6), 6.95 (1H, m, H-4), 720(1H, m, H-5), 7.40 (1H, dd, J=8.2, H-3).

Example 30b (4-Acetyl-2-chloro-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 30a usingthe procedure described in example 20b. Yield, 10%. Crude product waspurified by flash chromatography with 20% EtOAc in PE 60-80° C. mp,70-71° C.; MS (EI): 256 (M⁺), 241, 213 155; analysis: C₁₂H₁₃ClO₄requires C, 56.15; H, 5.07; Cl, 13.82. found, C, 56.24; H, 5.10; Cl,13.67%.

Example 30c (4-{2-Bromo-acetyl}-2-chloro-phenoxy)-acetic acid ethylester

The title compound was obtained from the compound of example 30b usingthe procedure described in example 20c. Purification was effected usingflash chromatography (silica gel, 40% EtOAc in PE60-80° C.). Yield, 46%;mp, 128-30° C.; MS (EI): (334,336) (M⁺), 241; analysis:

C₁₂H₁₂BrClO₄ requires C, 42.95; H, 3.60. found, C, 42.69; H, 3.45%.Example 30d(4-{2-tert-Butoxycarbonylamino-acetyl}-2-chloro-phenoxy)-acetic acidethyl ester

The title compound was obtained from the compound of example 30c usingthe procedure described in example 20d. Yield, 20%; mp, 75-76° C.; MS(EI): 371 (M⁺), 241; analysis: C₁₇H₂₂ClNO₆ requires C, 54.91; H, 5.92;N, 3.77; Cl, 9.54. found, C, 55.37; H, 6.00; N, 3.72; Cl, 9.94%.

Example 30e (4-{2-Amino-acetyl}-2-chloro-phenoxy)-acetic acid ethylester; hydrochloride

The title compound was obtained from the compound of example 30d usingthe procedure described in example 5b. Yield, 78%; mp, 163-64° C.; MS(EI): 271 (M⁺), 241; analysis: C₁₂H₁₃Cl₂NO₄ requires C, 46.77; H, 4.87;N, 4.55; Cl, 23.03. found, C, 47.12; H, 4.97; N, 4.36; Cl, 22.67%.

Example 30f(2-Chloro-4-{2-[5-cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 30e usingthe procedure described in example 1g. Yield, 11%, white solid; mp,178-80° C.; MS (EI): 412 (M⁺), 241; analysis: C₂₁H₁₇ClN₂O₅ requires C,61.10; H, 4.15; N, 6.74; Cl, 8.59. found, C, 60.90; 1-1, 4.23; N, 6.59;Cl, 8.60%.

Example 30g(2-Chloro-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 30F usingthe procedure described in example 1h. Yield, 86%, yellow solid; mp,85-87° C.; MS (ESI⁺): 468 (M⁺+Na), 446 (M⁺+1); analysis: C₂₁H₁₉ClN₂O₅Srequires C, 56.44; H, 4.29; N, 6.22; Cl, 7.93; S, 7.17. found, C, 56.01;H, 4.30; N, 6.01; Cl, 7.80; S, 7.60%.

Example 30h(2-Chloro-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 30g usingthe procedure described in example 1i. Yield, 91%, yellow solid; mp,155° C.; MS (ESI⁺): 468 (M⁺+Na), 461 (M⁺+1).

Example 31(2-Chloro-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 30 usingthe procedure described in example 6 Isobutyl chloroformate was usedinstead of methyl chloroformate. Yield, 42%, white solid; mp, 178-79°C.; MS (ESI⁺): 552 (M⁺+Na), 530 (M⁺+1); analysis: C₂₆H₂₈ClN₃O₇ requiresC, 58.93; H, 5.19; N, 7.93; Cl, 6.70. found, C, 59.37; H, 5.35; N, 7.98;Cl, 6.39%.

Example 32(2-Chloro-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 30h usingthe procedure described in example 4. Yield, 71%, white solid; mp,201-02° C.; MS (ESI⁺): 468 (M⁺+Na), 446 (M⁺+1); analysis: C₂₁H₂₀ClN₃O₆requires C, 56.57; H, 4.50; N, 9.43; Cl, 7.96. found, C, 56.53; H, 4.43;N, 9.11; Cl, 8.04%.

Example 33(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethylsulfanyl-phenoxy)-acetic acid ethyl ester, acetic acid salt, monohydrate

The title compound was obtained from the compound of example 33h usingthe procedure described in example 1. Yield, 24%, white solid; mp,185-86° C.; MS (ESI⁺): 478 (M⁺+Na), 456 (M⁺+1); analysis: C₂₅H₂₉N₃O₇S,H₂O requires C, 56.27; H, 5.67; N, 7.88; S, 6.01. found: C, 56.26; H,5.58; N, 8.20; S, 6.38%.

Example 33a 1-(3-Ethylsulfanyl-4-hydroxy-phenyl)-ethanone

The title compound was obtained from1-(3-bromo-4-hydroxy-phenyl)-ethanone using the procedure described inexample 29a. 1-Ethanethiolate Cu (I) was used instead ofmethyloxycarbonylmethanthiolate copper(I). It was purified using flashchromatography (silica gel, 10% EtOAc-PE60-80° C. Yield, 57%, brownishwhite solid; mp, 88° C.; MS (EI): 196 (M⁺), 181 (100%); analysis:C₁₀H₁₂O₂S requires C, 61.22; H, 6.12; S, 16.32. found C, 61.54; H, 6.35;S, 16.28%.

Example 33b (4-Acetyl-2-ethylsulfanyl-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 33a usingthe procedure described in example 20a. The crude product was purifiedusing flash chromatography (silica gel, 10% EtOAc in PE 60-80° C.).Yield, 89%, white solid; mp, 64-65° C.; MS (ESI): 305 (M⁺+Na), 283(M⁺+1); analysis: C₁₄H₁₈O₄S requires C, 59.57; H, 6.38; S, 11.35. foundC, 59.86; H, 6.49; S, 11.47%.

Example 33c (4-{2-Bromo-acetyl}-2-ethylsulfanyl-phenoxy)-acetic acidethyl ester

The title compound was obtained from the compound of example 33b usingthe procedure described in example 20c. Yield, 45%, white solid; mp, 84°C.; MS (EI): (360,362) (M⁺), 267 (100%); analysis: C₁₄H₁₇BrO₄S requiresC, 46.54; H, 4.71; Br, 22.16; S, 8.86. found: C, 46.90; H, 4.84; Br,21.87; S, 9.31%

Example 33d(4-{2-tert-Butoxycarbonylamino-acetyl}-2-ethylsulfanyl-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 33c usingthe procedure described in example 20d. Yield, 29%, white solid; mp, 83°C.; MS (EI): 397 (M⁺), 267 (100%), 253; analysis: C₁₉H₂₇NO₆S requires C,57.43; H, 6.80; N, 3.53; S, 8.06. found: C, 57.36; H, 6.80; N, 3.34; S,8.15%.

Example 33e (4-{2-Amino-acetyl}-2-ethylsulfanyl-phenoxy)-acetic acidethyl ester, hydrochloride

The title compound was obtained from the compound of example 33d usingthe procedure described in example 5b. Yield, 96%; MS (ESI): 298(M⁺-1-1); ¹H NMR (DMSO-D₆): 1.35 (6H, t, J=7.32, 2×CH₂CH ₃), 3.00 (2H,q, J=7.32, SCH ₂CH₃), 4.29 (2H, q, J=7.3, CH ₂CH₃), 4.65 (2H, d, CH₂NH), 4.80 (2H, s, OCH ₂), 6.75 (1H, d, J=9.14, H-5), 7.30 (3H, br, NH₃), 7.75 (1H, dd, J=9.14, H-6), 7.90 (1H, br, H-2).

Example 33f(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethylsulfanyl-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 33e usingthe procedure described in example 1g. Yield, 8%; mp, 157-60° C.; MS(ESI⁻): 437 (M−1); analysis: C₂₃H₂₂N₂O₅S requires C, 63.01; H, 5.02; N,6.39; S, 7.31. found: C, 63.26; H, 4.64; N, 6.49; S, 7.64%.

Example 33g(2-Ethylsulfanyl-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 33f usingthe procedure described in example 1h. Yield, 83%; mp, 178-79° C.; MS(ESI⁺): 495 (M⁺+Na), 473 (M⁺+1); analysis: C₂₃H₂₄N₂O₅S₂ requires C,58.46; H, 5.12; N, 5.93; S, 13.57. found: C, 58.40; H, 5.17; N, 5.99; S,13.62%.

Example 33h(2-Ethylsulfanyl-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 33g usingthe procedure described in example 11. Yield, 91%; mp, 182-83° C.; MS(ESI⁺): 508 (M⁺+Na), 487 (M⁺+1);

Example 34(2-Ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hemihydrate

The title compound was obtained from the compound of example 33h usingthe procedure described in example 4. Yield, 85%, white solid; mp,190-91° C.; MS (ESI⁺): 494 (M⁺+Na), 472 (M⁺+1); analysis: C₂₃H₂₅N₃O₆S,0.5H₂O, requires C, 57.50; H, 5.42; N, 8.75; S, 6.66. found: C, 57.88;H, 5.32; N, 9.10; S, 6.71%.

Example 35(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethanesulfonyl-phenoxy)-acetic acid ethyl ester; acetic acid salt, hydrate

The title compound was obtained from the compound of example 35e usingthe procedure described in example 1. Yield, 26% (white solid); mp,174-75° C.; MS (ESI⁺): 488 (M⁺+1); analysis: C₂₅H₂₉N₃O₉S, H₂O, requiresC, 53.10; H, 5.49; N, 7.43; S, 5.75. found: C, 52.40; H, 5.36; N, 7.08;S, 5.68%.

Example 35a(4-{2-tert-Butoxycarbonylamino-acetyl}-2-ethanesulfonyl-phenoxy)-aceticacid ethyl ester

A mixture of compound of example 33d (2.2 g; 5.54 mmol) and3-chloroperbenzoic acid (2.87 g; 16.62 mmol) in dichloromethane (10 ml)was stirred at room temperature until all the starting material wasconsumed. It was processed as is routinely done and was purified usingflash chromatography (silica gel, with 5% CH₃CN in chloroform). Yield, 2g (84%), foam; MS (ESI⁺): 430 (M⁺+1); analysis: C₁₉H₂₇NO₈S, requires C,58.14; H, 6.34; N, 3.26; S, 7.46. found: C, 58.51; H, 6.32; N, 3.25; S,7.40%.

Example 35b (4-{2-Amino-acetyl}-2-ethanesulfonyl-phenoxy)-acetic acidethyl ester, hydrochloride

The title compound was obtained from the compound of example 35a usingthe procedure described in example 5b Yield, 99%, pale yellow gum; MS(ESI⁺): 330 (M⁺+1); ¹H NMR (CDCl₃): 1.30 (6H, t, J=7.32, 2×CH₂CH ₃),3.50 (2H, q, J=7.32, SO₂CH ₂CH₃), 4.29 (2H, q, J=7.3, OCH ₂CH₃), 4.60(2H, d, NHCH ₂), 4.90 (2H, s, OCH ₂), 5.50 (1H, br, NHCH₂), 7.01 (1H, d,J=9.14, H-6), 8.21 (1H, dd, J=9.14, H-5), 8.60 (1H, br, H-3).

Example 35c(4-{2-[5-Cyano-t-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethanesulfonyl-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 35b usingthe procedure described in example 1g. Yield, 7%; mp, 194-95° C.; MS(ESI⁻): 469 (M−1); analysis: C₂₃H₂₂N₂O₇S requires C, 58.72; H, 4.68; N,5.96; S, 6.81. found: C, 58.97; H, 4.64; N, 5.72; S, 6.95%.

Example 35d(2-Ethanesulfonyl-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 35c usingthe procedure described in example 1h. Yield, 69%, yellow solid; mp,117-18° C.; MS (ESI⁺): 527 (M⁺+Na), 505 (M⁺+1); analysis: C₂₃H₂₄N₂O₇S₂,H₂O requires C, 52.87; H, 4.98; N, 5.36; S, 12.26. found: C, 52.61; H,4.61; N, 5.35; S, 12.35%.

Example 35e(2-Ethanesulfonyl-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 35d usingthe procedure described in example 11. Yield, 89%, yellow solid; mp,198-200° C.; MS (ESI⁺): 541 (M⁺+Na), 519 (M⁺+1).

Example 36(2-Ethanesulfonyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 35e usingthe procedure described in example 4. Yield, 70%, white solid; mp,196-97° C.; MS (ESI⁺): 526 (M⁺+Na), 504 (M⁺+1); analysis: C₂₃H₂₅N₃O₈Srequires C, 54.87; H, 4.97; N, 8.35; S, 6.36. found: C, 54.57; H, 4.84;N, 8.05; S, 6.66%.

Example 37(2,6-Bis-ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 37h usingthe procedure described in example 4. Yield, 37%; mp, 183-84° C.; MS(ESI⁺): 554 (M⁺+Na), 532 (M⁺+1); analysis: C₂₅H₂₉N₃O₆S₂ requires C,56.50; H, 5.46; N, 7.90; S, 12.05. found C, 56.90; H, 5.46; N, 8.01; S,12.30%.

Example 37a 1-(3,5-Bis-ethylsulfanyl-4-hydroxy-phenyl)-ethanone

Following the procedure for the preparation of example 29a,1-(3,5-dibromo-4-hydroxy-phenyl)-ethanone was treated with1-ethanethiolate Cu(I) in place of methyloxycarbonylmethanthiolatecopper (I) to obtain 37a. The crude product was purified by flashchromatography with 10% EtOAc in PE 60-80° C. Yield, 16%; mp, 74-75° C.;MS (EI): 256 (M⁺), 241, 213; analysis: C₁₂H₁₆O₂S₂ requires C, 56.25; H,6.25; S, 25.00. found C, 56.63; H, 6.47; S, 25.39%.

Example 37b (4-Acetyl-2,6-bis-ethylsulfanyl-phenoxy)-acetic acid ethylester

The title compound was obtained from the compound of example 37a usingthe procedure described in example 20a. It was purified using flashchromatography (silica gel, EtOAc in PE 60-80° C.). Yield, 80%, paleyellow liquid; MS (CI): 371 (M⁺+29), 343 (M⁺+1), 329; analysis:C₁₆H₂₂O₄S₂ requires C, 56.12; H, 6.47; S, 18.72. found C, 56.36; H,6.42; S, 18.69%.

Example 37c (4-{2-Bromo-acetyl}-2,6-bis-ethylsulfanyl-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 37b usingthe procedure described in example 20c. The crude product was purifiedusing flash chromatography (silica gel, 10% EtOAc in PE 60-80° C.).Yield, 80%, brown gum; MS (EI): (422, 420) (M⁺), (319, 317); analysis:C₁₆H₂₁BrO₄S₂ requires C, 45.61; H, 5.02; Br, 18.96; S, 15.22. found C,45.21; H, 4.98; Br, 18.60; S, 15.09%.

Example 37d(4-{2-tert-Butoxycarbonylamino-acetyl}-2,6-bis-ethylsulfanyl-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 37c usingthe procedure described in example 27a-b. The crude product was purifiedusing flash chromatography (silica gel, 10% EtOAc in PE 60-80° C.).Yield, 48%, pale yellow oil; MS (EI): 457 (M⁺), 425, 398; analysis:C₂₁H₃₁NO₆S₂ requires C, 55.12; H, 6.83; N, 3.06; S, 14.01. found C,54.93; H, 6.49; N, 2.98; S, 13.80%.

Example 37e (4-{2-Amino-acetyl}-2,6-bis-ethylsulfanyl-phenoxy)-aceticacid ethyl ester, hydrochloride

The title compound was obtained from the compound of example 37d usingthe procedure described in example 5b. Yield, 72%, yellow semisolid; MS(ESI): 358 (M⁺+1); analysis: C₁₆H₂₄ClNO₄S₂ requires C, 48.78; H, 6.14;N, 3.56; Cl, 9.00; S, 16.28. found C, 48.42; H, 6.05; N, 3.10; Cl, 8.90;S, 15.95%.

Example 37f(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2,6-bis-ethylsulfanyl-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 37e usingthe procedure described in example 1g. The crude was purified usingflash chromatography (silica gel, 5% CH₃CN in chloroform). Yield, 6%,white solid; MS (ESI): 521 (M⁺+Na), 499 (M⁺+1); analysis: C₂₅H₂₆ClN₂O₅S₂requires C, 60.22; H, 5.26; N, 5.62; S, 12.86. found C, 60.68; H, 5.20;N, 5.70; S, 12.90%.

Example 37g(2,6-Bis-ethylsulfanyl-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 37f usingthe procedure described in example 1h. Yield, 51%, yellow solid; mp,83-84° C.; MS (ESI): 531 (M−1); analysis: C₂₅H₂₈N₂O₅S₃ requires C,58.37; H, 5.30; N, 5.26; S, 18.06. found C, 58.51; H, 5.40; N, 5.28; S,18.10%.

Example 37h(2,6-Bis-ethylsulfanyl-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester hydroiodide

The title compound was obtained from the compound of example 37g usingthe procedure described in example a Yield, 98%, yellow solid.

Example 38(2-Acetylamino-4-{2-[5-N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 38h usingthe procedure described in example 1. Yield, 38%; mp, 185-86° C.; MS(ESI): 491 (M⁺+Na), 469 (M⁺-1-1); analysis: C₂₃H₂₄N₄O₇ requires C,58.97; H, 5.16; N, 11.96. found: C, 58.85; H, 5.14; N, 11.49%.

Example 38a N-(5-Acetyl-2-hydroxy-phenyl)-acetamide

A solution of 1-(4-hydroxy-3-nitro-phenyl)-ethanone (10 g) in methanol,DMF (50 ml) and acetic anhydride (10 ml) was hydrogenated using 10% Pd—C(0.45 g) for 2 h at 30 psi. The catalyst was filtered off. The filtratewas concentrated (5 ml) and treated with EtOAc (100 ml) to obtain thetitle compound, which was filtered, washed with EtOAc (10 ml) and dried.Yield, 9.1 g (85%); mp, >215° C.; MS (EI): 193 (M⁺), 151, 136, 108.

Example 38b (4-Acetyl-2-acetylamino-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 38a usingthe procedure described in example 20a, which was purified using flashchromatography (silica gel, 5-10% CH₃CN in chloroform). Yield, 60%; mp,113-14° C.; MS (ESI): 302 (M⁺+Na), 280 (M⁺+1); analysis: C₁₄H₁₇NO₅requires C, 60.21; H, 6.13; N, 5.02. found: C, 60.42; H, 6.24; N, 5.02%.

Example 38c (2-Acetylamino-4-{2-bromo-acetyl}-phenoxy)-acetic acid ethylester

The title compound was obtained from the compound of example 38b usingthe procedure described in example 20c. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN in chloroform). Yield,64%; mp, 124-25° C. (EtOAc-PE60-80° C.); MS (ESI): 380 (M⁺+Na), 358(M⁺+1); analysis: C₁₄H₁₆BrNO₅ requires C, 46.95; H, 4.50; N, 3.91; Br,22.31. found: C, 46.84; H, 4.15; N, 3.54; Br, 22.80%.

Example 38d(2-Acetylamino-4-{2-tert-butoxycarbonylamino-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 38c usingthe procedure described in example 20d. The crude product was purifiedusing flash chromatography (silica gel, 3-10% CH₃CN in chloroform).Yield, 35%, oil; ¹H NMR (CDCl₃): 1.30 (3H, t, J=7.5, CH₂CH ₃), 1.45 [9H,s, C(CH ₃)₃], 2.27 (3H, s, NHCOCH ₃), 4.30 (2H, q, J=7.5, CH ₂CH₃), 4.63(2H, d, J=5.4, COCH ₂NH), 4.74 (2H, s, OCH ₂), 5.5 (1H, br, NHCH₂), 6.97(1H, d, J=8.8, H-6), 7.69 (1H, dd, J=8.8, 2.0, H-5), 8.20 (1H, br,J=1.8, H-3), 9.00 (1H, br, NH).

Example 38e (2-Acetylamino-4-{2-amino-acetyl}-phenoxy)-acetic acid ethylester, hydrochloride

The title compound was obtained from the compound of example 38d usingthe procedure described in example 20e. Yield, 90%

Example 38f(2-Acetylamino-4-{2-[5-cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 38e usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN in chloroform, 1% MeOHin chloroform). Yield, 16%; mp, 121-22° C.

Example 38g(2-Acetylamino-4-{2-[1-oxo-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 38f usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN in chloroform, 1% MeOHin chloroform). Yield, 87%; mp, 110° C.

Example 38h(2-Acetylamino-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 38g usingthe procedure described in example 1i. Yield, 99%.

Example 39(2-{Ethoxycarbonylmethyl-methanesulfonyl-amino}-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, mono hydrate

The title compound was obtained from the compound of example 391 usingthe procedure described in example 6. Isobutyl chloroformate was usedinstead of methyl chloroformate. Yield, 63%; mp, 80-82° C.; MS (ESI):697 (M⁺+Na), 675 (M⁺+1); analysis: C₃₁H₃₈N₄O₁₁S H₂O requires, C, 53.75;H, 5.78; N, 8.09; S, 4.62. found C, 53.97; H, 5.57; N, 7.67; S, 4.14%.

Example 39a 1-(4-Benzyloxy-3-nitro-phenyl)-ethanone

1-(4-hydroxy-3-nitro-phenyl)-ethanone was treated with benzyl bromide inthe presence of K₂CO₃ in DMF, and processed as reported in the synthesisof example 20a to obtain the crude product which was purified usingflash chromatography (silica gel, 5% CH₃CN in chloroform). Yield, 94%;mp, 132° C.; MS (CI): 300 (M⁺+29), 272 (M⁺+1), 91; analysis: C₁₅H₁₃NO₄requires, C, 66.42; H, 4.83; N, 5.16. found; C, 66.58; H, 4.52; N,5.30%.

Example 39b 1-(3-Amino-4-benzyloxy-phenyl)-ethanone

The title compound was obtained from the compound of example 39a using areported procedure (Boruah. R. N., Ind. J. Chem., 33B, 758, 1994). Thecrude product was purified using flash chromatography (silica gel, 5%CH₃CN in chloroform). Yield, 76.9%; mp, 124-25° C.; MS (EI): 241 (M⁺),150, 91; analysis: C₁₅H₁₅NO₂ requires C, 74.67; H, 6.27; N, 5.80. found:C, 74.89; H, 6.45; N, 5.92%.

Example 39c N-(5-Acetyl-2-benzyloxy-phenyl)-methanesulfonamide

Methanesulfonyl chloride (6.08 ml; 78.5 mmol) was added drop wise over aperiod of 30 min. with vigorous stirring to a mixture of compound ofexample 39b (15.5 g; 64.32 mmol) in CH₂Cl₂ (200 ml) and pyridine (13.78ml; 165.7 mmol) at 0° C. The reaction mixture was slowly brought to roomtemperature and stirred overnight (˜16 h). It was acidified using dil.HCl and extracted with EtOAc. The EtOAc layer was washed with water,brine, dried (Na₂SO₄), concentrated and purified using flashchromatography (silica gel, 5% CH₃CN in chloroform). Yield, 17.5 g(85.3%); mp, 118-19° C.; MS (EI): 319 (M⁺), 240, 91; analysis:C₁₆H₁₇NO₄S requires C, 60.17; H, 5.36; N, 4.39; S, 10.04. found: C,60.30; H, 5.40; N, 4.44; S, 10.41%.

Example 39d N-(5-Acetyl-2-hydroxy-phenyl)-methanesulfonamide

In an atmosphere of nitrogen 10% Pd—C (1.17 g) was added to a mixture ofcompound of example 39c (11.7 g; 36.67 mmol) and ammonium formate (11.56g; 116.23 mmol) in methanol (110 mL) It was refluxed for 3 h. Thecatalyst was filtered and the filtrate concentrated and purified usingflash chromatography (silica gel, 10% CH₃CN in chloroform). Yield, 8.3 g(84.2%); mp, 202° C.: MS (ESI⁻): 228 (M−1); analysis: C₉H₁₁NO₄S requiresC, 47.15; H, 4.84; N, 6.11; S, 13.98. found: C, 47.39; H, 4.72; N, 6.53;S, 13.53%.

Example 39e(4-acetyl-2-{ethoxycarbonylmethyl-methansulfonyl-amino}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 39d usingthe procedure described in example 20a. Yield, 56%; MS (ESI): 424(M⁺+Na), 402 (M⁺+1); analysis: C₁₇H₂₃NO₈S requires C, 50.87; H, 5.77; N,3.49; S, 7.99. found: C, 51.29; H, 6.01; N, 3.08; S, 7.75%.

Example 39f(4-{2-Bromoacetyl}-2-{ethoxycarbonylmethyl-methane-sulfonyl-amino}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 39e usingthe procedure described in example 20c. The crude product was purifiedusing flash chromatography (silica gel, 5-10% CH₃CN in chloroform).Yield, 60%; MS (ESI): 504 (M⁺+Na), 482 (M⁺+1); ¹H NMR (CDCl₃): 1.32 (6H,m, 2×CH₂CH ₃), 3.16 (3H, s, SO₂CH ₃), 4.18, 4.27 (4H, 2×q, J=6.8, 2×CH₂CH₃), 4.42, 4.45, 4.84 (6H, 3×s, 3×CH ₂), 6.90 (1H, d, J=8.8, H-3),8.03 (1H, dd, J=8.5, 1.8, H-4), 8.27 (1H, d, J=1.8, H-6).

Example 39g(4-{2-tert-Butoxycarbonylamino-acetyl}-2-{ethoxycarbonylmethyl-methanesulfonyl-amino}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 39f usingthe procedure described in example 20d. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN in chloroform). Yield,28%; mp, 114-15° C.; MS (ESI): 538 (M⁺+Na).

Example 39h(4-{2-Amino-acetyl}-2-{ethoxycarbonylmethyl-methanesulfonyl-amino}-phenoxy)-aceticacid ethyl ester, hydrochloride

The title compound was obtained from the compound of example 39g usingthe procedure described in example 20e. Yield, 90%; mp, 187-90° C.; IR(KBr): 2950, 1750, 1600, 1475.

Example 39i(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethoxycarbonylmethyl-methanesulfonyl-amino)-phenoxy]-acetic acid ethyl ester

The title compound was obtained from the compound of example 39h usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN in chloroform, 1% MeOHin chloroform). Yield, 20%; mp, 170-71° C.; MS (ESI): 580 (M⁺+Na), 558(M⁺+1).

Example 39j(2-{Ethoxycarbonylmethyl-methanesulfonyl-amino}-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethylester

The title compound was obtained from the compound of example 39i usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN in chloroform, 2% MeOHin chloroform). Yield, 85%; mp, 96° C.; MS (ESI): 614 (M⁺+Na), 592(M⁺+1); analysis: C₂₆H₂₉N₃O₉S₂ requires, C, 52.78; H, 4.94; N, 7.10.found C, 52.58; H, 4.72; N, 7.49%.

Example 39k(2-{Ethoxycarbonylmethyl-methanesulfonyl-amino}-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 39j usingthe procedure described in example 1i. Yield, 98%.

Example 39l(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-{ethoxycarbonylmethyl-methanesulfonyl-amino}-phenoxy)-acetic acid ethyl ester, aceticacid salt

The title compound was obtained from the compound of example 39k usingthe procedure described in example 1. Yield, 25%; ¹H NMR (DMSO-D₆):1.18, 1.23 (6H, 2×t, J=7.5, 2×CH₂CH ₃), 1.78 (3H, s, CH ₃COO), 3.14 (3H,s, SO₂CH ₃), 4.10, 4.20 (4H, 2×q, J=6.8, 2-×CH ₂CH₃), 4.45, 4.63, 5.11,5.18 (8H, 4×s, 4×CH ₂), 7.28 (1H, d, J=8.9, H-3′), 7.92 (2H, br), 7.92,8.08, 8.14 (5H, m).

Example 40(2-{Ethoxycarbonylmethyl-methanesulfonyl-amino}-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 39k usingthe procedure described in example 4. Purification effected using flashchromatography (silica gel, 3% MeOH in chloroform). Yield, 45%; mp,165-67° C.; MS (ESI): 614 (M⁺+Na), 591 (M⁺+1); analysis: C₂₆H₃₀N₄O₁₀Srequires, C, 52.88; H, 5.12; N, 9.49; S, 5.43. found C, 52.53; H, 5.09;N, 9.06; S, 5.72%.

Example 41(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester, acetic acid salt

The title compound was obtained from the compound of example 41h usingthe procedure described in example 1. Yield, 40%, white solid; mp,195-96° C.; MS (ESI): 412 (M⁺+1), analysis: C₂₃H₂₅N₃O₈ requires C,58.60; H, 5.31; N, 8.92. found: C, 58.87; H, 5.36; N, 8.83%.

Example 41a (4-acetyl-3-hydroxy-phenoxy)-acetic acid ethyl ester Example41b (4-acetyl-3-ethoxycarbonylmethoxy-phenoxy)-acetic acid ethyl ester

1-(2,4-dihydroxy-phenyl)-ethanone was treated with 1 equivalent of ethyl2-bromoacetate and processed as described in the synthesis of example20a to obtain the desired title compounds. The crude mixture waspurified using flash chromatography (silica gel, 3% CH₃CN inchloroform).

41a: Yield, 57%; mp, 76-78° C.; MS (EI): 238 (M⁺), 223 (100%), 195, 165;analysis: C₁₂H₁₄O₅ requires C, 60.50; H, 5.92. found: C, 60.73; H,5.89%.

41b: Yield 15.4%; mp, 84-84.5° C.; MS (EI): 324 (M⁺), 309, 253, 223;analysis: C₁₆H₂₀O₇ requires C, 59.25; H, 6.22. found: C, 59.49; H,6.21%.

Example 41c (4-{2-Bromo-acetyl}-3-hydroxy-phenoxy)-acetic acid ethylester

The title compound was obtained by refluxing the compound of example 41awith CuBr₂ in EtOAc—CHCl₃ (1:1) as reported in the literature (L. C.King et. al. JOC, 1964, 29, 3459). The crude product was purified usingflash chromatography (silica gel, 3% CH₃CN in chloroform) andcrystallisation (EtOAc-PE60-80° C.). Yield, 54%; mp, 107-08° C.; MS(EI): (316, 318) (M⁺), 236, 223 (100%); analysis: C₁₂H₁₃BrO₅ requires C,45.45; H, 4.15. found: C, 45.69; H, 4.14%.

Example 41d (4-{2-Amino-acetyl}-3-hydroxy-phenoxy)-acetic acid ethylester, hydrochloride Example 41e(4-{2-tert-Butoxycarbonylamino-acetyl}-3-hydroxy-phenoxy)-acetic acidethyl ester

The compound of example 41c (14.88 g) was converted to the hexaminecomplex (21.5 g), then hydrolyzed with conc. HCl in EtOH using theprocedure described in example 1e. The solvent was removed and theresidue was stirred with water (50 ml) and filtered. It was washed withcold water (2×5 ml). and dried to give compound of example 41d. Yield,3.5 g (25.8%); mp, 189-92° C. (d); analysis: C₁₂H₁₆ClNO₅ requires C,49.75; H, 5.57; N, 4.83. found: C, 49.44; H, 5.93; N, 5.10%.

The filtrate was treated with di-tert-butyldicarbonate (13 g) using theprocedure described in example 16a. The crude product was purified usingflash chromatography (silica gel, 2% CH₃CN in chloroform) to obtaincompound of example 41e. Yield, 8.5 g (51.7%); mp, 46-48° C.; analysis:C₁₇H₂₃NO₇ requires C, 57.78; H, 6.56; N, 3.96. found: C, 58.18; H, 6.67;N, 3.86%.

Example 41f(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 41d usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN in chloroform). Yield,60%; mp, 193-95° C.; MS (EI): 394 (M⁺), 223 (100%), 195, 171; analysis:C₂₁H₁₈N₂O₆ requires C, 63.96; H, 4.60; N, 7.10. found: C, 63.51; H,4.57; N, 7.13%.

Example 41g(3-Hydroxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 41f usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN and 2% MeOH inchloroform). Yield, 96%, yellow solid; mp, 227-29° C.; MS (ESI): 451(M⁺+Na), 429 (M⁺+1); C₂₁H₂₀N₂O₆S requires C, 58.88; H, 4.67; N, 6.54; S,7.48. found: C, 59.14; H, 4.68; N, 6.29; S, 7.75%.

Example 41h(3-Hydroxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 41g usingthe procedure described in example 11. Yield, 56%, yellow solid; mp,167° C. (d); MS (ESI): 465 (M⁺+Na), 443 (M⁺+1).

Example 42(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 41h usingthe procedure described in example 4. The crude product was purifiedusing flash chromatography (silica gel, 8% MeOH in chloroform). Yield,75% (white solid); mp, 197-98° C.; MS (ESI⁻): 426 (M−1), analysis:C₂₁H₂₁N₃O₇ requires C, 59.02; H, 4.92; N, 9.84. found: C, 59.33; H,4.91; N, 9.44%.

Example 43(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid benzyl ester

The title compound was obtained from the compound of example 43g usingthe procedure described in example 4. The crude product was purifiedusing flash chromatography (silica gel, 4% MeOH in chloroform). Yield,89%, white solid; mp, 183-84° C.; MS (ESI⁺): 512 (M⁺+Na), 490 (M⁺+1);analysis: C₂₆H₂₃N₃O₇ requires C, 63.80; H, 4.74; N, 8.58. found: C,64.47; H, 4.84; N, 8.63%.

Example 43a (4-Acetyl-3-hydroxy-phenoxy)-acetic acid benzyl ester

1-(2,4-Dihydroxy-phenyl)-ethanone was treated with 1 equivalent ofbenzyl 2-bromoacetate and processed as described in the synthesis ofexample 20a to obtain the title compound. The crude was purified usingflash chromatography (silica gel, 3% CH₃CN in chloroform) andcrystallization was effected using ether-PE 60-80° C. Yield, 75%, whitesolid; mp, 66-67° C.; MS (EI): 300 (M⁺), 285, 165, 91 (100%); analysis:C₁₇H₁₆O₅ requires C, 67.99; H, 5.37. found: C, 67.99; H, 5.53%.

Example 43b (4-{2-Bromo-acetyl}-3-hydroxy-phenoxy)-acetic acid benzylester

The title compound was obtained from the compound of example 43a usingthe procedure as described in the synthesis of example 41c The crudeproduct was purified using flash chromatography (silica gel, 1%CH₃CN-chloroform: PE 60-80° C.) and crystallized from EtOAc-PE 60-80° C.Yield, 41%; mp, 98-99° C.; MS (EI): (380, 378) (M⁺), 298, 285; analysis:C₁₇H₁₅O₅Br requires C, 53.85; H, 3.99; Br, 21.07. found: C, 53.70; H,4.20; Br, 21.46%.

Example 43c(4-{2-tert-Butoxycarbonylamino-acetyl}-3-hydroxy-phenoxy)-acetic acidbenzyl ester

The title compound was obtained from the compound of example 43b usingthe procedure described in example 16a. The crude product was purifiedusing flash chromatography (silica gel, EtOAc PE 60-80° C.) andcrystallized from EtOAc-PE 60-80° C.). Yield, 7%; mp, 97-98° C.; MS(CI): 416 (M⁺+1); analysis: C₂₂H₂₅NO₇ requires C, 63.61; H, 6.07; N,3.37. found: C, 63.48; H, 6.17; N, 3.69%.

Example 43d (4-{2-Amino-acetyl}-3-hydroxy-phenoxy)-acetic acid benzylester; hydrochloride, sesquihydrate

The title compound was obtained from the compound of example 43c usingthe procedure described in example 5b. Yield, 91%, white solid; mp,160-61° C.; MS (ESI): 316 (M⁺+1); analysis: C₁₇H₁₈ClNO₅, 1.5H₂O requiresC, 53.86; H, 5.54; N, 3.70. found: C, 54.24; H, 5.82; N, 4.15%.

Example 43e(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid benzyl ester

The title compound was obtained from the compound of example 43d usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel 5% CH₃CN in chloroform). Yield,24%; mp, 211-13° C.; MS (ESI⁻): 455 (M−1); analysis: C₂₆H₂₀N₂O₆ requiresC, 68.42; H, 4.42; N, 6.14. found: C, 68.20; H, 4.09; N, 6.54%.

Example 43f (3-Hydroxy-4-{2-[1-oxo-5-thiocarbamoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acidbenzyl ester

The title compound was obtained from the compound of example 43e usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN and 1% MeOH inchloroform). Yield, 83%, yellow solid; mp, 152-53° C.; MS (ESI⁻): 489(M−1); analysis: C₂₆H₂₂N₂O₆S requires C, 63.66; H, 4.52; N, 5.71; S,6.54. found: C, 63.80; H, 4.44; N, 5.64; S, 6.28%.

Example 43g(3-Hydroxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester, hydroiodide

The title compound was obtained from the compound of example 43f usingthe procedure described in example 11. Yield, 94%, yellow solid; ¹H NMR(DMSO-D₆): 2.85 (3H, s, SCH ₃), 4.65, 5.0, 5.12, 5.22 (8H, 4×s, 4×CH ₂),6.55 (1H, br, H-2′), 6.60 (1H, dd, J=8.9, 2.0, H-6′), 7.40 (5H, br,PhH), 7.72 (1H, d, J=8.9, H-5′), 7.95 (2H, br, H-4 & H-6), 8.10 (1H, d,J=8.7, H-7), 11.60 (1H, s, OH).

Example 44(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid, trifluoroacetate

A mixture of the compound of example 43 (0.08 g; 0.163 mmol) and aceticanhydride (0.023 ml; 0.245 mmol) in glacial acetic acid (12 ml) wassubjected to hydrogenation over 10% Pd—C (0.02 g) at 15 psi for 15 min.Distilled TFA (5 ml) was added to obtain a clear solution. The catalystwas filtered off and the filtrate was evaporated to dryness. The crudeproduct was triturated with acetonitrile and ether twice to afford thetitle compound as a pure white solid. Yield, 0.045 g, (56%); mp, 262° C.(d); MS (ESI⁺): 384 (M⁺+1); analysis: C₂₁H₁₈N₃F₃O₈, 2H₂O requires C,47.29; H, 4.16; N, 7.88. found: C, 47.57; H, 4.06; N, 7.22%.

Example 45(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-methoxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 45e usingthe procedure described in example 4. The crude product was purifiedusing flash chromatography (silica gel, 1-2% MeOH in chloroform). Yield,25%, white solid; mp, 163-65° C.; MS (ESI⁺): 464 (M⁺+Na), 442 (M⁺+1);analysis: C₂₂H₂₃N₃O₇ requires C, 59.86; H, 5.25; N, 9.52. found: C,59.66; H, 4.92; N, 9.20%.

Example 45a(4-{2-tert-Butoxycarbonylamino-acetyl}-3-methoxy-phenoxy)-acetic acidethyl ester

To a vigorously stirred solution of the compound of example 41e (4.5 g;12.7 mmol) in dry DMF (20 ml) was added sequentially fused K₂CO₃ (3.5 g;25.5 mmol), methyl iodide (0.96 ml; 15.3 mmol) and KF (0.45 g). Thereaction mixture was stirred for 3 h, diluted with water (200 ml) andthe oily residue was extracted with chloroform (3×30 ml). The organiclayer was washed with brine, dried (Na₂SO₄), concentrated and purifiedusing flash chromatography (silica gel, 3% CH₃CN in chloroform). Yield,3.25 g (69.5%); mp, 75° C.; MS (ESI⁺): 390 (M⁺+Na), 368 (M⁺+1);analysis: C₁₈H₂₅NO₇ requires C, 58.85; H, 6.85; N, 3.81. found: C,58.79; H, 7.26; N, 3.81%.

Example 45b (4-{2-Amino-acetyl}-3-methoxy-phenoxy)-acetic acid ethylester, hydrochloride

The title compound was obtained from the compound of example 45a usingthe procedure described in example 5b.

Example 45c(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-methoxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 45b usingthe procedure described in example 1g.

The crude product was purified using flash chromatography (silica gel,10% CH₃CN in chloroform). Yield, 28%; mp, 182-83° C.; MS (CI): 437(M⁺+29), 409 (M⁺+1); analysis: C₂₂H₂₀N₂O₆, 1.5H₂O requires C, 60.63; H,5.28; N, 6.43. found: C, 60.97; H, 4.76; N, 6.42%.

Example 45d(3-Methoxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)aceticacid ethyl ester

The title compound was obtained from the compound of example 45c usingthe procedure described in example 1h.

The crude product was purified using flash chromatography (silica gel,2% MeOH in chloroform). Yield, 86%; mp, 172° C.; MS (ESI⁺): 465 (M⁺+Na),443 (M⁺+1); analysis: C₂₂H₂₂N₂O₆S requires C, 59.72; H, 5.01; N, 6.33;S, 7.25. found: C, 60.19; H, 5.39; N, 6.21; S, 72%.

Example 45e(3-Methoxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 45d usingthe procedure described in example 1i. Yield, 88%, crude product.

Example 46(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-propoxy-phenoxy)-aceticacid ethyl ester, monohydrate

The title compound was obtained from the compound of example 46e usingthe procedure described in example 4. The crude product was purifiedusing flash chromatography (silica gel, 1% MeOH in chloroform). Yield,58%, white solid; mp, 175-77° C.; MS (ESI⁺): 492 (M⁺+Na), 470 (M⁺+1);analysis: C₂₄H₂₇N₃O₇, H₂O requires C, 59.13; H, 5.90; N, 8.62. found: C,59.50; H, 5.48; N, 8.98%.

Example 46a(4-{2-tert-Butoxycarbonylamino-acetyl}-3-propoxy-phenoxy)-acetic acidethyl ester

The title compound was obtained from 1-bromopropane and the compound ofexample 41e using the procedure described in example 45a. Thepurification was carried out using flash chromatography (silica gel, 3%CH₃CN in chloroform). Yield, 66%, oil; analysis: C₂₀H₂₉NO₇ requires C,60.75; H, 7.39; N, 3.54. found: C, 61.18; H, 7.86; N, 3.81%.

Example 46b (4-{2-Amino-acetyl}-3-propoxy-phenoxy)-acetic acid ethylester, hydrochloride

The title compound was obtained from the compound of example 46a usingthe procedure described in example 5b.

Example 46c(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-propoxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 46b usingthe procedure described in example 1g. Yield, 13%; mp, 132-33° C.; MS(ESI⁺): 459 (M⁺+Na), 437 (M⁺+1).

Example 46d(4-{2-[1-Oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-3-propoxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 46c usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 1-2% MeOH in chloroform). Yield,98%; mp, 205° C.; MS (ESI⁻): 469 (M−1).

Example 46e(4-{2-[5-Methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-propoxy-phenoxy)-aceticacid ethyl ester; hydroiodide

The title compound was obtained from the compound of example 46d usingthe procedure described in example 1i. Yield, 98%, crude product.

Example 47(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxycarbonylmethoxy-phenoxy)-acetic acid ethyl ester, acetic acid salt,monohydrate

The title compound was obtained from the compound of example 47e usingthe procedure described in example 1. Yield, 13%; mp, 186-88° C.; MS(ESI⁺): 498 (M⁺+1); analysis: C₂₉H₃₁N₃O₁₀, H₂O requires: C, 57.19; H,5.82; N, 7.41. found: C, 57.02; H, 5.31; N, 7.55%.

Example 47a(4-{2-tert-Butoxycarbonylamino-acetyl}-3-ethoxycarbonylmethoxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from ethyl 2-bromoacetate and thecompound of example 41e using the procedure described in example 45a.Purification was carried out using flash chromatography (silica gel, 2%CH₃CN in chloroform). Yield, 83%, mp, 65-66° C.; MS (ESI⁺): 462 (M⁺+Na),440 (M⁺+1); analysis: C₂₁H₂₉NO₇ requires C, 57.40; H, 6.65; N, 3.19.found: C, 57.82; H, 7.04; N, 3.25%.

Example 47b (4-{2-Amino-acetyl}-3-ethoxycarbonylmethoxy-phenoxy)-aceticacid ethyl ester, hydrochloride

The title compound was obtained from the compound of example 47a usingthe procedure described in example 5b.

Example 47c(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxycarbonyl methoxy-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 47b usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 5-10% CH₃CN in chloroform).Yield, 16%; mp, 135-36° C.; MS (ESI⁺): 503 (M⁺+Na), 481 (M⁺+1);analysis: C₂₅H₂₄N₂O₈ requires: C, 62.50; H, 5.03; N, 5.83. found: C,62.22; H, 4.93; N, 6.33%.

Example 47d(3-Ethoxycarbonylmethoxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 47c usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 1-2% MeOH in chloroform. Yield,70%; MS (ESI⁺): 537 (M⁺+Na), 515 (M⁺+1).

Example 47e(3-Ethoxycarbonylmethoxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 47d usingthe procedure described in example 11. Yield, 98%, crude product.

Example 48(3-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 47e usingthe procedure described in example 4. Yield, 32%; mp, 139-40° C.; MS(ESI⁺): 536 (M⁺+Na), 514 (M⁺+1); analysis: C₂₅H₂₇N₃O₉, 0.5H₂O, requires:C, 57.47; H, 5.17; N, 8.04. found: C, 57.42; H, 5.07; N, 8.21%.

Example 49(2-Ethylsulfanyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 49g usingthe procedure described in example 4. Yield, 42%; mp, 182-83° C.; MS(ESI): 510 (M⁺+Na), 488 (M⁺+1); analysis: C₂₃H₂₅N₃O₇S requires C, 56.66;H, 5.17; N, 8.62; S, 6.58. found: C, 56.37; H, 5.47; N, 9.01; S, 6.18%.

Example 49a 1-(3-Ethylsulfanyl-2,4-dihydroxy-phenyl)-ethanone

NBS (53.4 g; 0.3 mol) was added over a period of 1 h to a solution of1-(2,4-dihydroxy-phenyl)-ethanone (45.6 g; 0.3 mol) in acetic acid (300ml). The reaction mixture was stirred overnight, treated with water (1.5lit.) and extracted with EtOAc. The EtOAc layer was washed with water,dried (Na₂SO₄), concentrated and purified using flash chromatography(silica gel, 3% CH₃CN in chloroform) to obtain a mixture of bromocompounds viz. 3-bromo, 5-bromo and 3,5-dibromo (53 g) and1-(2,4-dihydroxyphenyl)-1-ethanone (7 g). (Purification to separate thebromo compounds resulted in very poor yields).

The mixture was heated with CuSEt, quinoline and pyridine at 160-70° C.for 1.5 h following a reported procedure (refer R. Adams et. al., JACS,1951, 81, 4927-31). The crude product was purified using flashchromatography (silica gel, 10% EtOAc in PE60-80° C.) to obtain thetitle compound. Yield, 24%; mp, 42-44° C.; MS (EI): 212 (M⁺), 197, 137,109; analysis: C₁₀H₁₂O₃S requires C, 56.59; H, 5.70; S, 15.10. found: C,57.07; H, 6.47; S, 14.83%.

Two other compounds were also isolated:

1-(3,5-Bis-ethylsulfanyl-2,4-dihydroxy-phenyl)-ethanone

Yield, 14%; mp, 55-56° C.; MS (EI): 272 (M⁺), 257, 243, 143; analysis:C₁₇H₁₆O₃S₂ requires C, 52.12; H, 5.92; S, 23.54. found: C, 52.48; H,6.30; S, 23.71%.

1-(5-Ethylsulfanyl-2,4-dihydroxy-phenyl)-ethanone

Yield, 10%; mp, 74-76° C.; MS (EI): 212 (M⁺), 197, 183, 169, 113;analysis: C₁₀H₁₂O₃S requires C, 56.59; H, 5.70. found: C, 56.72; H,5.41%.

Example 49b (4-Acetyl-2-ethylsulfanyl-3-hydroxy-phenoxy)-acetic acidethyl ester

The title compound was obtained from the compound of example 49a usingthe procedure described in example 20a. It was purified using flashchromatography (silica gel, 10-20% EtOAc in PE 60-80° C.). Yield, 62%;mp, 48-50° C. (EtOAc-PE 60-80° C.); MS (EI): 298 (M⁺), 283, 265, 195(100%); analysis: C₁₄H₁₈O₅S requires C, 56.36; H, 6.08; S, 10.78. found:C, 56.64; H, 6.16; S, 11.38%.

Example 49c(4-{2-Bromo-acetyl}-2-ethylsulfanyl-3-hydroxy-phenoxy)-acetic acid ethylester

Compound of example 49b was treated with CuBr₂ following reportedprocedure (see example 41c) to obtain the title compound, which waspurified using flash chromatography (silica gel, 20% EtOAc in PE 60-80°C., 3% CH₃CN in dichloromethane). Yield, 33%; mp, 121-23° C. (EtOAc-PE60-80° C.); MS (EI): (376, 378) (M⁺), 297, 255, 193 (100%); analysis:C₁₄H₁₇BrO₅S requires C, 44.57; H, 4.54; Br, 21.18; S, 8.50. found: C,45.22; H, 4.58; Br, 21.29; S, 8.32%.

Example 49d(4-{2-Amino-acetyl}-2-ethylsulfanyl-3-hydroxy-phenoxy)-acetic acid ethylester, hydrochloride

The title compound was obtained from the compound of example 49c usingthe procedure described in example 41d. Yield, 51%; mp, 91-92° C.; MS(ESI): 336 (M⁺+Na), 312 (M⁺+1).

Example 49e(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethylsulfanyl-3-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 49d usingthe procedure described in example 1g. Yield, 26%; mp, 138-40° C.; MS(ESI): 477 (M⁺+Na), 455 (M⁺+1).

Example 49f(2-Ethylsulfanyl-3-hydroxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hemihydrate

The title compound was obtained from the compound of example 49e usingthe procedure described in example 1h. Yield, 75%; mp, 90° C.; MS (ESI):511 (M⁺+Na), 489 (M⁺+1); analysis: C₂₃H₂₄N₂O₄S₂, 0.5H₂O requires C,55.46; H, 5.02; N, 5.62. found: C, 55.05; H, 4.84; N, 4.94; S, 12.83%.

Example 49g(2-Ethylsulfanyl-3-hydroxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 49f usingthe procedure described in example 11. Yield, 98%.

Example 50(2-Ethyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 50g usingthe procedure described in example 4. Yield, 83%; mp, 218-19° C.; MS(ESI): 456 (M⁺+1); analysis: C₂₃H₂₅N₃O₇ requires C, 60.65; H, 5.53; N,9.23. found: C, 60.26; H, 5.51; N, 8.99%.

Example 50a (4-Acetyl-2-ethyl-5-hydroxy-phenoxy)-acetic acid ethyl ester

The title compound was obtained when1-(5-Ethyl-2,4-dihydroxy-phenyl)-ethanone was reacted with ethyl2-bromoacetate, and processed as described in the synthesis of example20a. Yield, 85.6%; mp, 89-90° C.; MS (EI): 266 (M⁺), 179.

Example 50b (4-{2-Bromo-acetyl}-2-ethyl-5-hydroxy-phenoxy)-acetic acidethyl ester

The compound of example 50a was treated with CuBr₂ following reportedprocedure (L. C. King et. al., JOC, 1964, 29, 3459-61). Yield, 57.3%; ¹HNMR (CDCl₃): 1.25 (3H, t, CH₂CH ₃), 1.30 (3H, t, OCH₂CH ₃), 2.65 (2H, q,CH ₂CH₃), 4.25 (2H, q, OCH ₂CH₃), 4.40 (2H, s, CH ₂Br), 4.7 (2H, s, OCH₂), 6.25 (1H, s, H-6), 7.5 (1H, s, H-3), 12.15 (1H, s, OH).

Example 50c(4-{2-tert-Butoxycarbonylamino-acetyl}-2-ethyl-5-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 50b usingthe procedure described in example 27a-b. Yield, 56.3%; ¹H NMR (CDCl₃):1.25 (3H, t, CH₂CH ₃), 1.30 (3H, t, OCH₂CH ₃), 1.6, [9H, s, C(CH ₃)₃],2.65 (2H, q, CH ₂CH₃), 4.25 (2H, q, OCH ₂CH₃), 4.65 (2H, s, OCH ₂), 4.7(2H, s, OCH ₂), 5.5 (1H, br, NH), 6.25 (1H, s, H-6), 7.45 (1H, s, H-3),12.0 (1H, s, OH).

Example 50d (4-{2-Amino-acetyl}-2-ethyl-5-hydroxy-phenoxy)-acetic acidethyl ester, hydrochloride

The title compound was obtained from the compound of example 50c usingthe procedure described in example 5b. Yield 74%.

Example 50e(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-yl]-acetyl}-2-ethyl-5-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 50d usingthe procedure described in example 1g. Yield, 28%; mp, 209-10° C.; MS(EI): 422 (M⁺), 251 (100%).

Example 50f(2-Ethyl-5-hydroxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 50e usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 1-2% MeOH in chloroform). Yield,70%; mp, 190-92° C.; MS (ESI): 457 (M⁺+1).

Example 50g(2-Ethyl-5-hydroxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 50f usingthe procedure described in example 11. MS (ESI): 471.5 (M⁺) ¹H NMR(CDCl₃+CD₃OD): 1.20 (3H, t, CH₂CH ₃), 1.25 (3H, t, OCH₂CH ₃), 2.65 (2H,q, CH ₂CH₃), 2.90 (3H, s, NH ₂, OH), 3.0 (3H, s, SCH ₃), 4.25 (2H, q,OCH ₂CH₃), 4.65, 4.70, 5.05 (6H, 3×s, 3×CH₂), 6.25 (1H, s, H-6′), 7.5(1H, s, H-3′), 7.90 (1H, dd, H-7), 8.05 (1H, d, H-6), 8.15 (1H, s, H-4).

Example 51(5-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isopropyl-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 51g in twosteps, using the procedures sequentially, described in example 1i and 4.The crude product was purified using flash chromatography (silica gel,10-20% CH₃CN in chloroform). Yield, 70%; mp, 207-09° C.; MS (ES³⁰): 492(M⁺+Na), 470 (M⁺+1); analysis: C₂₄H₂₇N₃O₇ requires C, 61.40; H, 5.80; N,8.95. found C, 61.80; H, 5.67; N, 8.93%.

Example 51a 1-(2,4-Dihydroxy-5-isopropyl-phenyl)-ethanone

Dry HCl was passed through a suspension of 4-isopropyl-1,3-benzenediol(17.01 g; 112 mmol), CH₃CN (8.3 ml; 158 mmol) and fused ZnCl₂ (14 g) indry ether (100 ml) for 1 h at 0° C. The reaction mixture was thenstirred for 1 h at room temperature and filtered. The solid obtained washydrolyzed with boiling water as reported in the literature. The crudeproduct was purified using flash chromatography (silica gel, 3% CH₃CN inchloroform). Yield, 15.2 g (69.6%); mp, 142-44° C.; MS (CI): 223(M⁺+29), 195 (M⁺+1), 179; analysis: C₁₁H₁₄O₃ requires: C, 68.02; H,7.26. found C, 68.40; H, 7.33%.

Example 51b (4-Acetyl-5-hydroxy-2-isopropyl-phenoxy)-acetic acid ethylester

The title compound was obtained from the compound of example 51a usingthe procedure described in example 20a. It was purified using flashchromatography (silica gel, chloroform/PE 60-80° C. (1:1) chloroform).Yield, 80%; mp, 70-72° C. (EtOAc-PE 60-80° C.); MS (EI): 280, 265(100%), 237, 191; analysis: C₁₅H₂₀O₅ requires: C, 64.27; H, 7.19. foundC, 64.86; H, 7.47%.

Example 51c (4-{2-Bromo-acetyl}-5-hydroxy-2-isopropyl-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 51b usingthe procedure described in example 50b. The crude product was purifiedusing flash chromatography (silica gel, 0.5% CH₃CN in chloroform: PE60-80° C. (4:6). Yield, 76%; mp, 94-95° C. (EtOAc-PE 60-80° C.); 1635;MS (EI): (358,360) (M⁺), (343,345), 265 (100%), 237, 191.

Example 51d(4-{2-tert-Butoxycarbonylamino-acetyl}-5-hydroxy-2-isopropyl-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 51c usingthe procedure described in example 27a-b. The crude product was purifiedusing flash chromatography (silica gel, 15% EtOAc in PE 60-80° C.).Yield, 47%; mp, 110-11° C. (EtOAc-PE 60-80° C.); MS (EI): 395 (M⁺), 339,265 (100%); analysis: C₂₀H₂₉NO₇ requires C, 60.70; H, 7.39; N, 3.54.found C, 61.11; H, 7.49; N, 2.98%.

Example 51e (4-{2-Amino-acetyl}-5-hydroxy-2-isopropyl-phenoxy)-aceticacid ethyl ester, hydrochloride

The title compound was obtained from the compound of example 51d usingthe procedure described in example 5b. Yield, 88%; MS (EI): 295 (M⁺),265 (100%), 237.

Example 51f(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-5-hydroxy-2-isopropyl-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 51e usingthe procedure described in example 1g. The crude product was purified byflash chromatography (silica gel, 5% CH₃CN in chloroform). Yield, 18%;mp, 195-96° C. (MeOH-ether); MS (CI): 465 (M⁺+29), 437 (M⁺+1), 265, 198,159; analysis: C₂₄H₂₄N₂O₆ requires C, 66.05; H, 5.54; N, 6.42. found C,66.34; H, 5.83; N, 6.39%.

Example 51g(5-Hydroxy-2-isopropyl-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 51f usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 1% MeOH in chloroform). Yield,76%; mp, 185-86° C. (MeOH-ether); MS (ES): 469 (M−1); analysis:C₂₄H₂₆N₂O₆S requires C, 61.26; H, 5.57; N, 5.95; S, 6.81. found C,61.80; H, 5.55; N, 5.72; S, 7.26%.

Example 52(2-tert-Butyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 52g usingthe procedure described in example 4. Yield, 92%, white solid; mp,177-78° C.; MS (ESI): 506 (M⁺+Na), 484 (M⁺+1); analysis: C₂₅H₂₉N₃O₇requires C, 60.91; H, 6.09; N, 8.52. found C, 60.74; H, 6.00; N, 8.45%.

Example 52a (4-Acetyl-2-tert-butyl)-5-hydroxy-phenoxy)-acetic acid ethylester

The title compound was obtained when1-(5-tert-Butyl-2,4-dihydroxy-phenyl)-ethanone was treated with ethyl2-bromoacetate and processed as described in the synthesis of example20a. Yield, 64%; mp, 110-11° C. (EtOAc-PE 60-80° C.); MS (CI): 323(M⁺+29), 295 (M⁺+1), 279, 267, 239; analysis: C₁₆H₂₂O₅ requires: C,65.29; H, 7.53. found C, 65.61; H, 7.85%.

Example 52b (4-{2-Bromo-acetyl}-2-tert-butyl-5-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 52a usingthe procedure described in example 50b. The crude product was purifiedusing flash chromatography (silica gel, 0.5% CH₃CN in chloroform: PE60-80° C. (4:6)). Yield, 71%; mp, 75-76° C. (EtOAc-PE 60-80° C.); MS(EI): (372, 374) (M⁺), (357, 359), 277; analysis: C₁₆H₂₁BrO₅ requires C,51.49; H, 5.67; Br, 21.41. found C, 51.44; H, 6.19; Br, 21.39%.

Example 52c(4-{2-tert-Butoxycarbonylamino-acetyl}-2-tert-butyl-5-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 52b usingthe procedure described in example 27a-b. The crude product was purifiedusing flash chromatography (silica gel, 15% EtOAc in PE 60-80° C.).Yield, 50%, oil; MS (CI): 438 (M⁺+29), 394, 382, 354 (100%); analysis:C₂₁H₃₁NO₇ requires C, 61.60; H, 7.63; N, 3.42. found C, 62.12; H, 7.46;N, 3.24%.

Example 52d (4-{2-Amino-acetyl}-2-tert-butyl-5-hydroxy-phenoxy)-aceticacid ethyl ester, hydrochloride

The title compound was obtained from the compound of example 52c usingthe procedure described in example 5b. Yield, 97%; MS (CI): 338 (M⁺+29),310 (M⁺+1), 292, 279; ¹H NMR (DMSO-D₆): 1.24 [3H, t, J=7.4, CH₂CH ₃),1.38 [9H, s, C(CH ₃)₃], 4.22 (2H, q, J=7.4, CH ₂CH₃), 4.37 (2H, d, NHCH₂), 4.90 (2H, s, OCH ₂), 6.53 (1H, s, H-3), 7.68 (1H, s, H-6), 8.27 (3H,br, NH ₃), 11.41 (1H, s, OH).

Example 52e(2-tert-Butyl-4-{2-[5-cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-5-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 52d usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 1-3% CH₃CN in chloroform).Yield, 37%; mp, 192-94° C. (EtOAc-PE 60-80° C.); MS (EI): 450 (M⁺), 279,251, 193, 171; analysis: C₂₅H₂₆N₂O₆ requires C, 66.66; H, 5.82; N, 6.22.found C, 67.12; H, 5.76; N, 6.15%.

Example 52f(2-tert-Butyl-5-hydroxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 52e usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN-1% MeOH inchloroform). Yield, 92%, yellow solid; mp, 203-04° C.; MS (ESI): 483(M⁺-1-1), 279, 251, 193, 171; analysis: C₂₅H₂₈N₂O₆S requires C, 61.97;H, 5.82; N, 5.78; S, 6.62. found C, 61.59; H, 5.96; N, 5.76; S, 6.98%.

Example 52g(2-tert-Butyl-5-hydroxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 52f usingthe procedure described in example 1i. Yield, 87%, yellow solid; mp,208-10° C.; MS (ESI⁻): 497 (M−1).

Example 53(2-Chloro-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hemihydrate

The title compound was obtained from the compound of example 53i usingthe procedure described in example 4. Yield, 46%; mp, 227-28° C.; MS(ESI⁻): 460 (M⁺−1); analysis: C₂₁H₂₀ClN₃O₇, 0.5H₂O requires C, 53.52; H,4.46; N, 8.91. found: C, 53.61; H, 4.42; N, 8.61%.

Example 53a 1-(5-Chloro-2,4-dihydroxy-phenyl)-ethanone Example 53b1-(3-Chloro-2,4-dihydroxy-phenyl)-ethanone

N-chlorosuccinimide (19.31 g; 144.5 mmol) in DMF (20 ml) was added dropwise over a period of 10 min. with stirring to a mixture of1-(2,4-dihydroxy-phenyl)-ethanone (20 g; 131.46 mmol), glacial aceticacid (105 ml) and DMF (26 ml) at 0° C. The reaction mixture was stirredovernight (˜16 h) at room temperature. It was diluted with water andextracted with EtOAc. The organic layer was washed with water, dried(Na₂SO₄), concentrated and purified using flash chromatography (silicagel, 30% EtOAc in PE 60-80° C.). Crystallization using EtOAc-PE 60-80°C. gave the pure products.

53a: Yield, 7.7 g (31%), white solid; mp, 165-67° C.; MS (CI): 187, 189(M⁺+1).

53b: Yield, 9.4 g (38%), white solid; MS (CI): 187, 189 (M⁺+1).

Example 53c (4-Acetyl-2-chloro-5-hydroxy-phenoxy)-acetic acid ethylester

The title compound was obtained from the compound of example 53a usingthe procedure described in example 20a. Yield, 39%, white solid; mp,140° C.; MS (EI): 272 (M⁺), 257, 208; analysis: C₁₂H₁₃ClO₅ requires C,52.86; H, 4.81; Cl, 13.00. found: C, 53.33; H, 4.81; Cl, 13.17%.

Example 53d (4-{2-Bromo-acetyl}-2-chloro-5-hydroxy-phenoxy)-acetic acidethyl ester

The title compound was obtained from the compound of example 53c usingthe procedure described in example 50b. Yield, 65%, white solid; mp,112-14° C.; MS (EI): (352, 354) (M⁺), 257 (100%), 259; analysis:C₁₂H₁₂BrClO₅ requires C, 41.00; H, 3.44; halogen, 32.81. found: C,41.43; H, 3.86; halogen, 33.08%.

Example 53e(4-{2-tert-Butoxycarbonylamino-acetyl}-2-chloro-5-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 53d usingthe procedure described in example 20d (1.5N ethanolic HCl was usedinstead of 1.5 N aqueous HCl). Yield, 37%, white solid; mp, 109-10° C.;MS (ESI): 410 (M⁺+Na); analysis: C₁₇H₂₂ClO₇ requires C, 52.65; H, 5.72;N, 3.61; Cl, 9.14. found: C, 52.26; H, 5.85; N, 3.93; Cl, 8.89%.

Example 53f (4-{2-Amino-acetyl}-2-chloro-5-hydroxy-phenoxy)-acetic acidethyl ester, hydrochloride

The title compound was obtained from the compound of example 53e usingthe procedure described in example 5b. Yield, 90%, white solid; mp,239-41° C. (d); MS (ESI): 310 (M⁺+Na), 288 (M⁺+1).

Example 53g(2-Chloro-4-{2-[5-cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-5-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 53f usingthe procedure described in example 1g. Yield, 5%, white solid; mp,214-15° C.; MS (CI): 457 (M⁺+29), 429 (M⁺+1).

Example 53h(2-Chloro-5-hydroxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 53g usingthe procedure described in example 1h. Yield, 69%, yellow solid; mp,227-29° C.; MS (ESI): 485 (M⁺+Na), 463 (M⁺+1).

Example 53i(2-Chloro-5-hydroxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 53h usingthe procedure described in example 11. Yield, 96%, yellow solid; mp,173-75° C. (d); MS (ESI): 477 (M⁺+1).

Example 54(2-Chloro-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hemihydrate

The title compound was obtained from the compound of example 54g usingthe procedure described in example 4. Yield, 47%, white solid; mp,214-15° C.; MS (ESI): 484 (M⁺+Na), 462 (M⁺+1); analysis: C₂₁H₂₀ClN₃O₇,0.5H₂O requires C, 53.52; H, 4.46; N, 8.91. found: C, 53.71; H, 4.34; N,8.74%.

Example 54a (4-Acetyl-2-chloro-3-hydroxy-phenoxy)-acetic acid ethylester

The title compound was obtained from the compound of example 53b usingthe procedure described in example 20a. Yield, 50%, white solid; mp,110-11° C.; MS (CI): 301 (M⁺+29), 273 (M⁺+1); analysis: C₁₂H₁₃ClO₅requires C, 52.86; H, 4.81; Cl, 13.00. found: C, 53.42; H, 5.00; Cl,13.19%.

Example 54b (4-{2-Bromo-acetyl}-2-chloro-3-hydroxy-phenoxy)-acetic acidethyl ester

The title compound was obtained from the compound of example 54a usingthe procedure described in example 50b. Yield, 65%, white solid; mp,137-38° C.; MS (EI): (352, 354) (M⁺), 259, 257 (100%); analysis:C₁₂H₁₂BrClO₅ requires C, 41.00; H, 3.44; halogen, 32.81. found: C,41.54; H, 3.54; halogen, 33.35%.

Example 54c(4-{2-tert-Butoxycarbonylamino-acetyl}-2-chloro-3-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 54b usingthe procedure described in example 20d (1.5N ethanolic HCl was usedinstead of 1.5N aqueous HCl). Yield, 37%, white solid; mp, 109-10° C.;MS (CI): 416 (M⁺+29), 388 (M⁺+1); analysis: C₁₇H₂₂ClO₇ requires C,52.65; H, 5.72; N, 3.61; Cl, 9.14. found: C, 52.16; H, 5.85; N, 3.93;Cl, 8.89%.

Example 54d (4-{2-Amino-acetyl}-2-chloro-3-hydroxy-phenoxy)-acetic acidethyl ester, hydrochloride

The title compound was obtained from the compound of example 54c usingthe procedure described in example 5b. Yield, 99%, white solid; mp,198-200° C.; MS (ESI): 288 (M⁺+1); analysis: C₁₂H₁₄ClNO₅ requires C,43.22; H, 4.80; N, 4.20; Cl, 21.28. found C, 43.04; H, 4.70; N, 4.75;Cl, 21.23%.

Example 54e(2-Chloro-4-{2-[5-cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 54d usingthe procedure described in example 1g. Yield, 4%, white solid; mp,227-29° C.; MS (ESI): 451 (M⁺+Na), 429 (M⁺+1); analysis: C₂₁H₁₇ClN₂O₆requires C, 56.38; H, 4.25; N, 6.27. found C, 56.31; H, 4.12; N, 5.87%.

Example 54f(2-Chloro-3-hydroxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 54e usingthe procedure described in example 1h. Yield, 63%, yellow solid; mp,186-88° C.; (ESI): 485 (M⁺+Na), 463 (M⁺+1); analysis: C₂₁H₁₉ClN₂O₆Srequires C, 54.49; H, 4.14; N, 6.05. found C, 54.09; H, 4.31; N, 5.84%.

Example 54g(2-Chloro-3-hydroxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 54f usingthe procedure described in example 11. Yield, 86%, yellow solid; mp,195-97° C.; MS (ESI): 477 (M⁺+1).

Example 55(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid ethyl ester, hydrate

The title compound was obtained from the compound of example 55f in twosteps, using the procedures sequentially, described in examples 1i and4. Yield, 22%; mp, 226-28° C.; MS (ES⁺): 464 (M⁺+Na), 442 (M⁺+1);analysis: C₂₂H₂₃N₃O₇, H₂O requires C, 57.51; H, 5.48; N, 9.15; found C,57.15; H, 5.11; N, 8.83%.

Example 55a 1-(2,4-Dihydroxy-3-methyl-phenyl)-ethanone

A mixture of 2-methyl-benzene-1,3-diol, acetic anhydride and ZnCl₂ washeated at 150-60° C. for 3.5 h, and processed as reported in theliterature. (Pearson. D. E. et. al., Synthesis, 533, 1972 and thereferences cited therein). The crude was purified using flashchromatography (silica gel, 0-5% CH₃CN in chloroform) to obtain thetitle compound. Yield, 73%; mp, 65-66° C. (EtOAc-PE 60-80° C.); MS (CI):195 (M⁺+29), 169 (M⁺+1); analysis: C₉H₁₀O₃ requires C, 65.05; H, 6.07.found C, 65.44; H, 6.62%.

Example 55b (4-Acetyl-3-hydroxy-2-methyl-phenoxy)-acetic acid ethylester

The title compound was obtained from the compound of example 55a usingthe procedure described in example 20a. The crude was purified usingflash chromatography (silica gel, 3% CH₃CN in chloroform). Yield, 87%;mp, 58-60° C. (EtOAc-PE 60-80° C.); MS (EI): 252 (M⁺), 237 (100%), 208,178, 164; analysis: C₁₃H₁₆O₅ requires C, 61.90; H, 6.39. found C, 61.55;H, 6.60%.

Example 55c (4-{2-Bromo-acetyl}-3-hydroxy-2-methyl-phenoxy)-acetic acidethyl ester

The title compound was obtained from the compound of example 55b usingthe procedure described in example 50b. The crude was purified usingflash chromatography (silica gel, 1-2% CH₃CN in chloroform). Yield, 61%;mp, 117° C. (hot EtOAc-PE 60-80° C.); MS (EI): (332, 330) (M⁺), 237(100%), 208.

Example 55d (4-{2-Amino-acetyl}-3-hydroxy-2-methyl-phenoxy)-acetic acidethyl ester, hydrochloride

The title compound was obtained from the compound of example 55c usingthe procedure described in example 41d. Yield, 86%; mp, 201-03° C.; MS(CI): 296 (M⁺+29), 268 (M⁺).

Example 55e(4-{2-[5-cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-methyl-phenoxy)-aceticacid ethyl ester, hemihydrate

The title compound was obtained from the compound of example 55d usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN in chloroform). Yield,21%; mp, 224-25° C. (EtOAc-PE60-80° C.); MS (EI): 450 (M⁺), 279, 251,193, 171; analysis: C₂₂H₂₀N₂O₆, 0.5H₂O requires C, 63.30; H, 5.07; N,6.71. found C, 62.99; H, 4.94; N, 6.59%.

Example 55f(3-Hydroxy-2-methyl-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 55e usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 25% CH₃CN in chloroform). Yield,65%; mp, 210-12° C. (EtOAc-PE60-80° C.); MS (ESI): 465 (M⁺+Na), 443(M⁺+1); analysis: C₂₂H₂₂N₂O₆S requires C, 59.72; H, 5.01; N, 6.33; S,7.25. found C, 60.05; H, 5.26; N, 6.14; S, 7.57%.

Example 56(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-acetic acid benzyl ester,hemihydrate

The title compound was obtained from the compound of example 56f in twosteps, using the procedures sequentially, described in examples 1i and4. Mp, 200° C.; MS (ESI): 504 (M⁺+1); analysis. C₂₇H₂₅N₃O₇, 0.5H₂Orequires, C, 63.27; H, 5.11; N, 8.20. found, C, 63.50; H, 4.87; N,8.16%.

Example 56a(4-{2-tert-Butoxycarbonylamino-acetyl}-3-hydroxy-2-methyl-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 55d usingthe procedure described in example 27b. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN in chloroform). Yield,86%; MS (ESI): 390 (M⁺+Na), 368 (M⁺+1).

Example 56b(4-{2-tert-Butoxycarbonylamino-acetyl}-3-hydroxy-2-methyl-phenoxy)-aceticacid

The compound of example 56a was hydrolyzed using 1N methanolic NaOH toobtain the title compound, which was purified using flash chromatography(silica gel, 5% CH₃CN in chloroform). Yield, 82.5%; MS (ESI): 362(M⁺+Na), 340 (M⁺+1).

Example 56c(4-{2-tert-Butoxycarbonylamino-acetyl}-3-hydroxy-2-methyl-phenoxy)-aceticacid benzyl ester

The title compound was obtained from the compound of example 56b usingthe procedure described in example 5a (benzyl alcohol was used insteadof isopropanol). The crude product was purified by flash chromatography(silica gel, 2% CH₃CN in chloroform). Yield, 87.4%; MS (ESI): 475(M⁺+Na), 452 (M⁺+1); analysis. C₂₃H₂₇NO₇ requires C, 64.32; H, 6.34; N,3.26. found, C, 63.67; H, 6.05; N, 3.32%.

Example 56d (4-{2-Amino-acetyl}-3-hydroxy-2-methyl-phenoxy)-acetic acidbenzyl ester; hydrochloride

The title compound was obtained from the compound of Example 56c usingthe procedure described in example 5b. Yield, 71%.

Example 56e(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-methyl-phenoxy)-aceticacid benzyl ester

The title compound was obtained from the compound of example 56d usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN in chloroform). Yield,38.7%; mp, 212° C.; MS (CI): 499 (M⁺+29), 471 (M⁺+1), 407, 299, 199,159, 91 (100%).

Example 56f(3-Hydroxy-2-methyl-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester

The title compound was obtained from the compound of example 56e usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 25% CH₃CN in chloroform). Yield,67.5%, yellow solid; mp, 207° C.; analysis C₂₇H₂₄N₂O₆S requires, C,64.27; H, 4.99; N, 5.55. found, C, 63.28; H, 4.91; N, 5.42%.

Example 57(2-Ethyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 57g usingthe procedure described in example 4. Yield, 72%; mp, 196-97° C.;analysis: C₂₃H₂₅N₃O₇ requires C, 60.65; H, 5.53; N, 9.23. found: C,60.58; H, 5.75; N, 8.74%.

Example 57a (4-Acetyl-2-ethyl-3-hydroxy-phenoxy)-acetic acid ethyl ester

1-(3-Ethyl-2,4-dihydroxy-phenyl)-ethanone was treated with2-bromo-acetic acid ethyl ester and processed as described in thesynthesis of example 20a. Yield, 96.89%; mp, 74-75° C.; MS (CI): 267(M⁺+1).

Example 57b (4-{2-Bromo-acetyl}-2-ethyl-3-hydroxy-phenoxy)-acetic acidethyl ester

The title compound was obtained from the compound of example 57a usingthe procedure described in example 50b. Yield, 47%; ¹H NMR (CDCl₃): 1.1(3H, t, CH₂CH ₃), 1.30 (3H, t, J=7.3, OCH₂CH ₃), 2.75 (2H, q, J=7.3,CH₂CH ₃), 4.25 (2H, q, J=7.3, OCH ₂CH₃), 4.4 (2H, s, BrCH ₂), 4.75 (2H,s, OCH ₂CO), 6.3 (1H, d, H-6), 7.6 (1H, d, J=8.5, H-5), 12.77 (1H, s, 2

Example 57c(4-{2-tert-Butoxcarbonylamino-acetyl}-2-ethyl-3-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 57b usingthe procedure described in example 41e. Yield, 60%; MS (CI): 382 (M+1).

Example 57d (4-{2-Amino-acetyl}-2-ethyl-3-hydroxy-phenoxy)-acetic acidethyl ester; hydrochloride

The title compound was obtained from the compound of example 57c usingthe procedure described in example 5b. Yield, 65%.

Example 57e(4-{2-[5-cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethyl-3-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 57d usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN in chloroform). Yield,17.4%; mp, 178-79° C.; MS (CI): 423 (M⁺+1).

Example 57f(2-Ethyl-3-hydroxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 57e usingthe procedure described in example 1h. Yield, 86.4%, yellow solid; mp,156-57° C.; MS (ESI⁻): 455 (M−1).

Example 57g(2-Ethyl-3-hydroxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 57f usingthe procedure described in example 11. Yield, 98%, yellow solid; mp74-75° C.

Example 58(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 58g usingthe procedure described in example 4. The crude product was purifiedusing flash chromatography (silica gel, 3% MeOH in chloroform). Yield,70%, white solid; mp, 211-12° C.; MS (ESI): 492 (M⁺+Na), 470 (M⁺4-1);analysis: C₂₄H₂₇N₃O₇ requires C, 61.40; H, 5.80; N, 8.95. found C,61.60; H, 5.84; N, 8.68%.

Example 58a (4-Acetyl-3-hydroxy-2-propyl-phenoxy)-acetic acid ethylester

1-(2,4-Dihydroxy-3-propyl-phenyl)-ethanone was treated with ethyl2-bromoacetate and processed as described in the synthesis of example20a. Yield, 80%, white solid; mp, 61-62° C.; MS (EI): 280 (M⁺), 265, 251(100%), 193; analysis: C₁₅H₂₀O₅ requires C, 64.27; H, 7.19. found: C,64.56; H, 7.39%.

Example 58b (4-{2-Bromo-acetyl}-3-hydroxy-2-propyl-phenoxy)-acetic acidethyl ester

The title compound was obtained from the compound of example 58a usingthe procedure described in example 50b. Yield, 50%, white solid; mp,120-21° C.; MS (EI): (358, 360) (M⁺), (231, 229), 279, 265 (100%);analysis: C₁₅H₁₉BrO₅ requires C, 50.16; H, 5.33; Br, 22.24. found: C,50.47; H, 5.32; Br, 21.89%.

Example 58c(4-{2-tert-Butoxycarbonylamino-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 58b usingthe procedure described in example 20b (1.5N ethanolic HCl was usedinstead of 1.5N aqueous HCl). Yield, 40%, white solid; mp, 80-83° C.; MS(CI): 396 (M⁺+1), 340, 296 (100%); analysis: C₂₀H₂₉NO₇ requires C,60.75; H, 7.39; N, 3.54. found: C, 61.00; H, 7.52; N, 3.52%.

Example 58d (4-{2-Amino-acetyl}-3-hydroxy-2-propyl-phenoxy)-acetic acidethyl ester, hydrochloride

The title compound was obtained from the compound of example 58c usingthe procedure described in example 5b. Yield, 91%, white solid; mp,188-190° C.; MS (ESI): 288 (M⁺+1); analysis: C₁₅H₂₂ClNO₅ requires C,54.30; H, 6.68; N, 4.22; Cl, 10.69. found: C, 54.20; H, 6.50; N, 3.98;Cl, 10.50%.

Example 58e(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 58d usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN in chloroform). Yield,39%, white solid; mp, 136-37° C.; MS (ESI): 437 (M⁺+1); analysis:C₂₄H₂₄N₂O₆ requires C, 66.05; H, 5.54; N, 6.42. found C, 66.05; H, 5.49;N, 6.13%.

Example 58f(3-Hydroxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 58e usingthe procedure described in example 1h. Purification was effected usingflash chromatography (silica gel, 5% MeOH in chloroform). Yield, 73%,yellow solid; mp, 194-95° C.; MS (ESI): 493 (M⁺+Na), 471 (M⁺+1);analysis: C₂₄H₂₆N₂O₆S requires C, 61.26; H, 5.57; N, 5.95; S, 6.81.found C, 61.17; H, 5.54; N, 5.75; S, 7.09%.

Example 58g(3-Hydroxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 58f usingthe procedure described in example 11. Yield, 98%, yellow solid; MS(ESI): 485 (M⁺+1); ¹H NMR (DMSO-D₆): 0.90 (3H, t, J=7.6, CH₂CH₂CH ₃),1.25 (3H, t, J=7.6, OCH₂CH ₃), 1.52 (2H, m, CH₂CH ₂CH₃), 2.65 (2H, t,J=7.6, CH ₂CH₂CH₃), 2.85 (3H, s, SCH ₃), 4.2 (2H, q, J=7.6, OCH ₂CH₃),4.65, 5.05, 5.20 (6H, 3×s, 3×CH ₂), 6.65 (1H, d, J=10.2, H-6′), 7.95(4H, m), 8.19 (1H, br), 12.2 (1H, s, OH).

Example 59(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-acetic acid benzyl ester

The title compound was obtained from the compound of example 59e usingthe procedure described in example 4. The crude product was purifiedusing flash chromatography (silica gel, 3% MeOH in chloroform). Yield,80%, white solid; mp, 199-200° C.; MS (ESI): 554 (M⁺+Na), 532 (M⁺+1);analysis: C₂₉H₂₉N₃O₇ requires C, 63.53; H, 5.50; N, 7.91. found C,65.20; H, 5.48; N, 7.70%.

Example 59a(4-{2-tert-Butoxycarbonylamino-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid benzyl ester

The compound of example 58c was hydrolyzed using 1N methanolic NaOH. Theacid obtained was converted into the title compound as described in thepreparation of example 5a. Benzyl alcohol was used instead ofisopropanol. Yield, 81%, white solid; mp, 112-13° C.; MS (EI): 457 (M⁺),401, 327 (100%), 91; analysis: C₂₅H₃₁NO₇ requires C, 65.63; H, 6.83; N,3.06. found: C, 66.14, H, 6.93; N, 3.07%.

Example 59b (4-{2-Amino-acetyl}-3-hydroxy-2-propyl-phenoxy)-acetic acidbenzyl ester, hydrochloride

The title compound was obtained from the compound of example 59a usingthe procedure described in example 5b.

Example 59c(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid benzyl ester

The title compound was obtained from the compound of example 59b usingthe procedure described in example 1g and was purified using flashchromatography (silica gel, 5% CH₃CN in chloroform). Yield, 33%, whitesolid; mp, 198-99° C.; MS (ESI): 521 (M⁺+Na), 499 (M⁺+1); analysis:C₂₄H₂₆N₂O₆ requires C, 69.87; H, 5.26; N, 5.62. found C, 69.97; H, 5.16;N, 5.52%.

Example 59d(3-Hydroxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid benzyl ester

The title compound was obtained from the compound of example 59c usingthe procedure described in example 1h. Purification was effected usingflash chromatography (silica gel, 10% CH₃CN+5% MeOH in chloroform).Yield, 91%, yellow solid; mp, 170-71° C.; MS (ESI): 555 (M⁺+Na), 533(M⁺+1); analysis: C₂₉H₂₈N₂O₆S requires C, 65.40; H, 5.30; N, 5.26; S,6.02. found C, 65.76; H, 5.08; N, 5.27; S, 6.39%.

Example 59e(3-Hydroxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid benzyl ester, hydroiodide

The title compound was obtained from the compound of example 59d usingthe procedure described in Example 1i. Yield, 87%, yellow solid; mp,175-76° C.; MS (ESI): 569 (M⁺+Na), 547 (M⁺+1); analysis: C₃₀H₃₁IN₂O₆Srequires C, 53.42; H, 4.63; N, 4.15; S, 4.75; I, 18.81. found C, 54.08;H, 4.65; N, 4.06; S, 5.07; I, 19.00%.

Example 60(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid, trifluoroacetic acid salt

The compound of example 59 was hydrogenated using 10% Pd—C, as describedin example 17. TFA was added to dissolve the precipitated compound.Filtration and concentration afforded the title compound. Yield, 80%,white solid; mp, 222-23° C.; MS (ESI): 426 (M⁺+1); analysis:C₂₄H₂₄F₃N₃O₈ requires C, 53.44; H, 4.48; N, 7.79. found C, 52.89; H,4.70; N, 7.39%.

Example 61(4-Hydroxy-3-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 61g usingthe procedure described in example 4. The crude product was purified byflash chromatography (silica gel, 3% MeOH in chloroform). Yield, 34%,white solid; mp, 158-59° C.; MS (ESI): 450 (M⁺+Na), 428 (M⁺+1);analysis: C₂₁H₂₁N₃O₇ requires C, 59.01; H, 4.95; N, 9.83. found: C,58.95; H, 5.03; N, 9.58%.

Example 61a (3-Acetyl-4-hydroxy-phenoxy)-acetic acid ethyl ester

K₂CO₃ (15.43 g; 112 mmol) was added in small portions over 30 min to asolution of 1-(2,5-dihydroxy-phenyl)-ethanone (11.33 g; 74.47 mmol) andethyl 2-bromoacetate (8.29 ml; 75 mmol) in DMF (40 ml). The reactionmixture was stirred at room temperature for 2 h, and then processed. Thecrude product obtained was purified using flash chromatography (silicagel, 2% CH₃CN in chloroform). Yield, 6.0 g (33.8%); mp, 60° C. (EtOAc-PE60-80° C.); MS (EI): 238 (M^(a)), 223, 195, 151 (100%); analysis:C₁₂H₁₄O₅ requires C, 60.50; H, 5.92. found: C, 60.57; H, 6.10%.

Example 61b (3-{2-Bromo-acetyl}-4-hydroxy-phenoxy)-acetic acid ethylester

The title compound was obtained from the compound of example 61a usingthe procedure described in example 50b. The crude product was purifiedusing flash chromatography (silica gel, dichloromethane: PE 60-80°C.::60:40). Yield, 68%; mp, 120-22° C. (EtOAc-PE 60-80° C.); MS (EI):316, 318 (M⁺), 236, 223, 195, 163; analysis: C₁₂H₁₃BrO₅ requires C,45.45; H, 4.13. found: C, 45.67; H, 4.16%.

Example 61c(3-{2-tert-Butoxycarbonylamino-acetyl}-4-hydroxy-phenoxy)-acetic acidethyl ester

The title compound was obtained from the compound of example 61b usingthe procedure described in example 16a (1.5N alcoholic HCl was usedinstead of 1.5N aqueous HCl). The crude product was purified by flashchromatography (silica gel, 3% CH₃CN in chloroform). Yield, 52.4%; mp,91-93° C. (EtOAc-PE 60-80° C.); MS (ESI⁺): 376 (M⁺+Na), 354 (W+1);analysis: C₁₇H₂₃NO₇ requires C, 57.78; H, 6.56; N, 3.96. found: C,58.87; H, 6.61; N, 3.66%.

Example 61d (3-{2-Amino-acetyl}-4-hydroxy-phenoxy)-acetic acid ethylester, hydrochloride

The title compound was obtained from the compound of example 61c usingthe procedure described in example 5b.

Example 61e(3-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-4-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 61d usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN in chloroform). Yield,16%; mp, 182° C. (EtOAc); MS (ESI⁺): 417 (M⁺+Na), 395 (M⁺+1); analysis:C₂₁H₁₈N₂O₆ requires C, 63.96; H, 4.60; N, 7.10. found: C, 63.83; H,4.47; N, 7.11%.

Example 61f(4-Hydroxy-3-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 61e usingthe procedure described in example 1h. The crude product was purified byflash chromatography with 10% CH₃CN and 1% MeOH in chloroform. Yield,60%; MS (ESI⁺): 451 (M⁺+Na), 429 (M⁺+1).

Example 61g(4-Hydroxy-3-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 61f usingthe procedure described in example 11.

Example 62(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-5-methoxy-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 62g usingthe procedure described in example 4. The crude product was purifiedusing flash chromatography (silica gel, 3% MeOH in chloroform). Yield,0.061 g (73%), white solid; mp, 209-10° C.; MS (ESI): 480 (M⁺+Na), 458(M⁺+1), (ESI⁻): 456 (M−1); analysis: C₂₂H₂₃N₃O₈ requires: C, 57.77; H,5.07; N, 9.19. found: C, 57.36; H, 5.09; N, 9.21%.

Example 62a Cyanomethyl-carbamic acid benzyl ester

To a vigorously stirred solution of aminoacetonitrile (20 g; 0.216mole), NaHCO₃ (50 g; 0.595 mole) in water (450 ml) and dioxane (250 ml),50% benzyl chloroformate in toluene (67.88 ml; 0.475 mole) was added at0° C. After stirring at room temperature for 16 h, the reaction mixturewas extracted with EtOAc. The EtOAc layer was washed with water anddried over anhydrous Na₂SO₄. Solvent was removed and the dark brown oilwas purified by flash chromatography over silica gel with 30-50%EtOAc-PE 60-80° C. Yield, 33 g (80.3%); mp, 42-43° C.; MS (EI): 190(M⁺), 145, 130, 117, 108, 91; analysis: C₁₀H₁₀N₂O₂ requires C, 63.15; H,5.30; N, 14.73. found: C, 62.95; H, 5.05; N, 14.50%.

Example 62b (2-{2,4-Dihydroxy-6-methoxy-phenyl}-2-oxo-ethyl)-carbamicacid benzyl ester

Dry HCl gas was passed through a suspension of5-methoxy-benzene-1,3-diol (11 g; 78.49 mmol), 62a (16.42 g; 86.36 mmol)and fused ZnCl₂ (1.96 g) in dry ether (40 ml), for 1 h at 0° C. Thereaction mixture was kept at 0° C. overnight (˜16 h). The ether wasdecanted and the yellow residue was hydrolyzed with water as reported inliterature (J. S. H. Davies, JCS, 1950, 3206-13). The title compoundobtained was purified using flash chromatography (silica gel, 5%CH₃CN—CHCl₃.) Yield, 10 g (28%); mp, 147-48° C.; MS (EI): 331 (M⁺), 167(100%); analysis: C₁₇H₁₇NO₆ requires: C, 61.63; H, 5.17; N, 4.23. found:C, 61.20; H, 4.85; N, 4.0%.

Example 62c(4-{2-Benzyloxycarbonylamino-acetyl}-3-hydroxy-5-methoxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 62b usingthe procedure described in example 20a. The crude product was purifiedusing flash chromatography (silica gel, 30% EtOAc-PE 60-80° C.). Yield,6.3 g (50%); mp, 113-14° C.; MS (EI): 417 (M), 253 (100%); analysis:C₂₁H₂₃NO₈ requires: C, 61.43; H, 5.55; N, 3.36. found: C, 61.24; H,4.98; N, 3.63%.

Example 62d (4-{2-Amino-acetyl}-3-hydroxy-5-methoxy-phenoxy)-acetic acidethyl ester, hydrobromide

A mixture of 62c (0.72 g, 1.725 mmol), glacial acetic acid (0.353 ml)and 33% HBr in AcOH (1.06 ml) was stirred at room temperature for 30min. The solvent was removed and the dark brown oil obtained wastriturated with dry ether to afford the title compound as a brownishwhite solid. Yield, 0.6 g (95%); mp, 175-76° C.; MS (EI): 283 (M⁺), 253(100%); analysis: C₁₃H₁₈BrNO₈ requires: C, 42.87; H, 4.98; N, 3.85; Br,21.94. found: C, 42.44; H, 5.01; N, 3.68; Br, 22.02%.

Example 62e(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-5-methoxy-phenoxy)-aceticacid ethyl ester, hemihydrate

The title compound was obtained from the compound of example 62d usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN in chloroform). Yield,0.156 g (6%); mp, 209-10° C.; MS (EI): 424 (M⁺), 253 (100%); analysis:C₂₂H₂₀NO₇.0.5H₂O requires: C, 60.91; H, 4.85; N, 6.46. found: C, 60.76;H, 4.29; N, 6.37%.

Example 62f(3-Hydroxy-5-methoxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, monohydrate

The title compound was obtained from the compound of example 62e usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN, 1% MeOH inchloroform). Yield, 0.143 g (91%), yellow solid; mp, 150-52° C.; MS(ESI): 457 (M−1); analysis: C₂₂H₂₂N₂O₇, H₂O requires: C, 55.40; H, 5.04;N, 5.88; S, 6.71. found: C, 55.81; H, 4.93; N, 6.30; S, 7.02%.

Example 62g(3-Hydroxy-5-methoxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 62f usingthe procedure described in example 1i. Yield, 0.128 g (79%), yellowsolid; mp, 152-54° C.; MS (ESI⁺): 495 (M⁺+Na), 473 (M⁺+1); analysis:C₂₃H₂₅IN₂O₇S. requires C, 46.01; H, 4.20; N, 4.67; S, 5.34; I, 21.14.found: C, 45.98; H, 4.21; N, 4.86; S, 5.64; I, 21.10%.

Example 63(3,5-Dihydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 63h usingthe procedure described in example 4. The crude product was purifiedusing flash chromatography (silica gel, 3-5% MeOH in CHCl₃). Yield, 0.03g (33%), white solid; mp, 229-30° C.; MS (ESI⁺): 466 (M⁺+Na), 444(M⁺+1), analysis: C₂₁H₂₁N₃O₈. requires C, 56.88; H, 4.77; N, 9.48.found: C, 56.50; H, 4.77; N, 8.96%.

Example 63a Acetic acid 3-acetoxy-5-benzyloxy-phenyl ester

Water (4.3 ml, 236 mmol) in DMF (20 ml) was added drop wise at roomtemperature with stirring to a mixture of acetic acid3,5-diacetoxy-phenyl ester (refer Kawamoto. H. et. al. Synth. Commun. M,531, 1996) (35 g, 139 mmol), NaH (5.66 g, 236 mmol) and benzyl chloride(19.16 ml, 166 mmol) in dry DMF (300 ml). The reaction mixture wasstirred overnight (˜16 h), poured into chilled dil. aqueous HCl andextracted with CH₂Cl₂ to obtain the crude title compound which waspurified using flash chromatography (silica ge, 20-50% CH₂Cl₂ in PE60-80° C.). Yield, 12.5 g (30%), white solid; mp: 129-30° C.; MS (EI):300 (M⁺), 258, 216, 91 (100%); analysis: C₁₇H₁₆O₅ requires: C, 67.99; H,5.37 found: C, 67.50; H, 5.40%.

Example 63b 5-Benzyloxy-benzene-1,3-diol

The compound in example 63a was treated with 1N methanolic NaOH for 1 h.The reaction mixture was processed and the crude product obtained waspurified using flash chromatography (silica gel, 20% EtOAc in PE 60-80°C.). Yield, 93%, white solid; mp: 85-86° C.; MS (EI): 216 (M⁺), 91(100%); analysis: C₁₃H₁₂O₃ requires: C, 72.21; H, 5.59 found: C, 72.51;H, 6.05%.

Example 63c (2-{2-Benzyloxy-4,6-dihydroxy-phenyl}-2-oxo-ethyl)-carbamicacid benzyl ester

The title compound was obtained from the compound of example 63b usingthe procedure described in example 62a-b. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN in chloroform). Yield,35%, white solid; mp: 129-31° C.; MS (ESI: 430 (M⁺+Na), 408 (M⁺+1),(ESI⁻): 406 (M−1); analysis: C₂₃H₂₁NO₆ requires: C, 67.81; H, 5.20; N,3.42. found: C, 67.89; H, 5.10; N, 3.09%.

Example 63d(3-Benzyloxy-4-{2-benzyloxycarbonylamino-acetyl}-5-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 63c usingthe procedure described in example 20a. It was purified using flashchromatography (silica gel, chloroform). Yield, 70%, white solid; mp,140-41° C.; MS (CI): 522. (M⁺+29), 494 (M⁺+1); analysis: C₂₇H₂₇NO₈requires: C, 65.71; H, 5.51; N, 2.84. found: C, 66.07; H, 6.03; N,2.98%.

Example 63e (4-{2-Amino-acetyl}-3,5-dihydroxy-phenoxy)-acetic acid ethylester, hydrochloride

The compound of example 63d (3.5 g; 7.09 mmol) in glacial acetic (150ml) was hydrogenated using 10% Pd—C (1 g) at 15 psi for 30 min. Thecatalyst was filtered, the filtrate was evaporated to dryness and thecrude product obtained was triturated with ethereal HCl and washed withdry ether to afford the title compound as white solid. Yield, 2 g (92%);mp: 225-27° C.; MS (ESI⁻): 268. (M−1); analysis: C₁₂H₁₆ClNO₆ requires:C, 47.15; H, 5.28; N, 4.58; Cl, 11.60. found: C, 46.63; H, 5.05; N,4.29; Cl, 11.50%.

Example 63f(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3,5-dihydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 63e usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN, 2% MeOH in CHCl₃).Yield, 0.55 g (23%), white solid, mp, >260° C.; MS (ESI⁺): 411 (M⁺+1);analysis: C₂₁H₁₈N₂O₇. requires: C, 61.46; H, 4.42; N, 6.83. found: C,62.24; H, 4.42; N, 6.83%.

Example 63g(3,5-Dihydroxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 63f usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 5-10% CH₃CN in CHCl₃). Yield,97%, yellow solid; mp: 260° C. (d); MS (ESI⁺): 467 (M⁺+Na), 445 (M⁺+1);analysis: C₂₁H₂₀N₂O₇S requires: C, 56.75; H, 4.54; N, 6.30; S, 7.21.found: C, 57.11; H, 4.72; N, 6.07; S, 7.02%.

Example 63h(3,5-Dihydroxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 63g usingthe procedure described in example 1i. Yield, 97%, yellow solid; mp, 95°C. (d); MS (ESI⁺): 482 (M⁺+Na), 459 (M⁺+1).

Example 64(2-Ethoxycarbonylmethoxy-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceicacid ethyl ester

The title compound was obtained from the compound of example 64f in twosteps, using the procedures sequentially, described in examples 1i and4. The crude product was purified using flash chromatography (silicagel, 3% MeOH in chloroform). Yield, 48%, white solid; mp, 153-55° C.; MS(ESI): 552 (M⁺+Na).

Example 64a (4-Acetyl-2-ethoxycarbonylmethoxy-3-hydroxy-phenoxy)-aceticacid ethyl ester

1-(2,3,4-Trihydroxy-phenyl)-ethanone was treated with 2-bromo-aceticacid ethyl ester in the presence of K₂CO₃ and processed as described inthe synthesis of example 20a. The crude product was purified using flashchromatography (silica gel, 20% EtOAc in PE 60-80° C.). Yield, 69.2%,oil; MS (EI): 341 (M⁺+1), 279, 267, 193, 165; analysis: C₁₆H₂₀O₈requires C, 56.47; H, 5.92. found: C, 56.91; H, 6.32%.

Example 64b(4-{2-Bromo-acetyl}-2-ethoxycarbonylmethoxy-3-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 64a usingthe procedure described in example 50b. The crude product was purifiedusing flash chromatography (silica gel, 20% EtOAc in PE 60-80° C.).Yield, 61%; MS (EI): 418, 420 (M⁺), 338, 265, 250, 191, and 165.

Example 64c[4-(2-tert-Butoxycarbonylamino-acetyl)-2-ethoxycarbonylmethoxy-3-hydroxy-phenoxy]-aceticacid ethyl ester

The title compound was obtained from the compound of example 64b usingthe procedure described in example 20d (1.5N alcoholic HCl was usedinstead of 1.5N aqueous HCl). The crude product was purified using flashchromatography (silica gel, 20-30% EtOAc in PE 60-80° C.). Yield, 58%,oil; MS (ESI⁺): 478 (M⁺+Na), 456 (M⁺+1); analysis: C₂₁H₂₉NO₁₀ requiresC, 55.38; H, 6.42; N, 3.06. found: C, 55.78; H, 6.85; N, 3.43%.

Example 64d[4-(2-Amino-acetyl)-2-ethoxycarbonylmethoxy-3-hydroxy-phenoxy]-aceticacid ethyl ester, hydrochloride

The title compound was obtained from the compound of example 64c usingthe procedure described in example 5b.

Example 64e(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethyoxycarbonylmethoxy-3-hydroxy-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 64d usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 5% CH₃CN in chloroform). Yield,14%; mp, 136-38° C. (EtOAc); MS (ESI⁻): 495 (M−1).

Example 64f(2-Ethoxycarbonylmethoxy-3-hydroxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 64e usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN, 1% MeOH inchloroform). Yield 72%; mp, 76° C.; MS (ESI⁺): 553 (M⁺+Na); analysis:C₂₅H₂₆N₂O₉S requires C, 56.60; H, 4.94; N, 5.28. found: C, 57.02; H,4.62; N, 5.03%.

Example 65(2-Ethoxycarbonylmethoxy-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, sesquihydrate

The title compound was obtained from the compound of example 65i in twosteps, using the procedures sequentially, described in examples 1i and4. It was purified using flash chromatography with 3% MeOH inchloroform. Yield, 26%, white solid; mp, 186-88° C.; MS (ESI): 552(M⁺+Na), 520 (M⁺+1); analysis: C₂₅H₂₇N₃O₁₀, 1.5H₂O requires C, 53.90; H,5.39; N, 7.55. found: C, 53.96; H, 5.12; N, 7.33%.

Example 65a (2-Ethoxycarbonylmethoxy-4-formyl-phenoxy)-acetic acid ethylester

3,4-Dihydroxy-benzaldehyde was treated with 2-bromo-acetic acid ethylester in the presence of K₂CO₃ and processed as described in thesynthesis of example 20a. The crude product was purified using flashchromatography (silica gel, 30-50% EtOAc in PE 60-80° C.). Yield, 87%;mp, 56° C. (EtOAc-PE 60-80° C.); MS (EI): 310 (M⁺), 237, 163, 149;analysis: C₁₅H₁₈O₇, 0.5H₂O requires C, 56.37; H, 5.95. found: C, 56.72;H, 5.79%.

Example 65b (2-Ethoxycarbonylmethoxy-4-hydroxy-phenoxy)-acetic acidethyl ester

The compound of example 65a obtained above was treated with3-chlorobenzoic acid in dichloromethane as reported in the literature(I. M. Godfrey et. al, JCS Perkin I, 1974, 1353,). The formyl esterobtained was purified using column chromatography (neutral alumina, 3-5%MeOH in dichloromethane) and crystallized from EtOAc-PE 60-80° C. Yield,68%; mp, 67° C. (EtOAc-PE 60-80° C.); MS (EI): 298 (M⁺); analysis:C₁₄H₁₈O₇ requires C, 56.37; H, 6.08. found: C, 56.12; H, 5.89%.

Example 65c (4-Allyloxy-2-ethoxycarbonylmethoxy-phenoxy)-acetic acidethyl ester

Allyl bromide (25.53 ml; 302 mmol) was added slowly to a mixture of thecompound of example 65b (75 g; 251.4 mmol), K₂CO₃ (52.04 g; 377 mmol)and KI (˜1 g) in DMF (150 ml) under vigorous stirring for 15 min at roomtemperature. The reaction mixture was stirred overnight (˜16 h), treatedwith water (1 lit.), and extracted with EtOAc. The EtOAc layer waswashed with water, brine, dried (Na₂SO₄), concentrated and purifiedusing flash chromatography (silica gel, 3% CH₃CN in chloroform) toobtain the title compound as an oil. Yield, 76 g (89.7%); MS (EI): 337(M⁺), 136.

Example 65d (4-Acetyl-2-ethoxycarbonylmethoxy-5-hydroxy-phenoxy)-aceticacid ethyl ester

The compound of example 65c (38 g; 112.5 mmol) was heated with acetylchloride (9.74 ml; 137 mmol) and activated Zn (7.46 g) in toluene (250ml) for 5 h (Synth. Commun, 1998, 28, 2203). to obtain the titlecompound which was processed as is routinely done and purified usingflash chromatography (silica gel, 3% CH₃CN in chloroform). Yield, 30 g(78.3%); MS (CI): 409 (M⁺+29), 381(M⁺); analysis: C₁₆H₂₀O₈ requires C,56.47; H, 5.92. found: C, 56.05; H, 5.59%.

Example 65e(4-{2-Bromo-acetyl}-2-ethoxycarbonylmethoxy-5-hydroxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 65d usingthe procedure described in example 50b. The crude product was purifiedusing flash chromatography (silica gel, with 3% CH₃CN in chloroform).Yield, 50%; MS (CI): 447 (M⁺+29), 419 (M⁺+1); analysis: C₁₆H₁₉BrO₈requires C, 45.84; H, 4.57; Br, 19.06. found: C, 45.45; H, 4.26; Br,18.91%.

Example 65f4-(2-tert-Butoxycarbonylamino-acetyl)-2-ethoxycarbonylmethoxy-5-hydroxy-phenoxy]-aceticacid ethyl ester

The title compound was obtained from the compound of example 65e usingthe procedure described in example 16a (1.5N alcoholic HCl was usedinstead of 1.5N aqueous HCl). The crude product was purified using flashchromatography (silica gel, 3% CH ₃CN in chloroform). Yield, 30%; mp,73-74° C.; MS (ESI⁺): 478 (M⁺+Na), 456 (M⁺+1); analysis: C₂₁H₂₉NO₁₀requires C, 55.38; H, 6.42; N, 3.06. found: C, 55.69; H, 6.74; N, 3.19%.

Example 65g(4-{2-Amino-acetyl}-2-ethoxycarbonylmethoxy-5-hydroxy-phenoxy)-aceticacid ethyl ester, hydrochloride

The title compound was obtained from the compound of example 65f usingthe procedure described in example 5b.

Example 65h(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethoxycarbonylmethoxy-5-hydroxy-phenoxy)-acetic acid ethyl ester

The title compound was obtained from the compound of example 65g usingthe procedure described in example 1g. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN in chloroform, 1% MeOHin chloroform). Yield, 22%; mp 168-69° C. (EtOAc); MS (ESI⁺): 519(M⁺+23), 497(M⁺+1); analysis: C₂₅H₂₄N₂O₉, 2H₂O requires C, 56.34; H,5.20; N, 5.25. found: C, 56.60; H, 4.86; N, 5.19%.

Example 65i(2-Ethoxycarbonylmethoxy-5-hydroxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 65h usingthe procedure described in example 1h. The crude product was purifiedusing flash chromatography (silica gel, 10% CH₃CN, 1% MeOH inchloroform). Yield, 94%; mp 142-43° C.; MS (ESI⁺): 553 (M⁺+Na),531(M⁺+1); analysis: C₂₅H₂₆N₂O₉S requires C, 56.60; H, 4.94; N, 5.28.found: C, 56.82; H, 4.71; N, 5.23%.

Example 66(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperazine-1-yl)-aceticacid ethyl ester; acetic acid salt

The title compound was obtained from the compound of example 66f bysubjecting it to hydrogenation in AcOH and ethanol over 10% Pd—C, usingthe procedure reported in the literature (see Gante. J. et. al. Bioorg.Med. Chem. 6, 2425, 1996). The title compound was purified using anRP-18 column (40% MeOH in water containing 0.2% AcOH). Yield, 39.5%; mp,211-12° C.; MS (ESI⁺): 388 (M⁺+1), analysis: C₂₁H₂₉N₅O₆ requires C,56.38; H, 6.49; N, 15.66. found: C, 55.57; H, 6.34; N, 15.02%.

Example 66a (5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl)-acetic acid ethylester

The title compound was obtained from Glycine ethyl ester hydrochlorideusing the procedure described in example 1g. It was purified using flashchromatography (silica gel, 3.5% CH₃CN in chloroform). Yield 88%; mp,105° C.; MS (EI): 244 (M⁺), 170, 114; analysis: C₁₃H₁₂N₂O₃ requires: C,63.93; H, 4.95; N, 11.47. found: C, 63.48; H, 4.54; N, 11.35%.

Example 66b(5-{N-Hydroxycarbamimidoyl}-1-oxo-1,3-dihydro-isoindol-2-yl)-acetic acidethyl ester

A mixture of the compound of example 66a (1.85 g; 8 mmol), hydroxylaminehydrochloride (2.21 g; 31.82 mmol) and Na₂CO₃ (1.55 g; 14.62 mmol) inmethanol (14.3 ml) and water (43 ml) was refluxed in an atmosphere ofnitrogen for 3 h. It was concentrated and extracted with EtOAc. Theorganic layer was dried (Na₂SO₄), concentrated and purified bytrturation with EtOAc and PE 60-80° C. to obtain the title compound.Yield, 1 g (47%); mp, 150-51° C.; MS (ESI): 286 (M⁺+Na), analysis:C₁₂H₁₃N₃O₄ requires C, 54.75; H, 4.98; N, 15.96. found: C, 54.70; H,4.92; N, 15.89%.

Example 66C(5-{5-Methyl-[1,2,4]oxadiazol-3-yl}-1-oxo-1,3-dihydro-isoindol-2-yl)-aceticacid ethyl ester

The compound of example 66b (1 g; 3.8 mmol) in acetic anhydride (20 ml)was heated at 120° C. for 4 h. It was concentrated and purified usingflash chromatography (silica gel, 5% CH₃CN in dichloromethane) to obtainthe title compound. Yield, 0.6 g (55%); mp, 155° C.; MS (ESI⁻): 286(M−1), analysis: C₁₄H₁₃N₃O₄ requires C, 58.53; H, 4.56; N, 14.63. found:C, 58.13; H, 4.79; N, 14.14%.

Example 66d(5-{5-Methyl-[1,2,4]oxadiazol-3-yl}-1-oxo-1,3-dihydro-isoindol-2-yl)-aceticacid

A solution of the compound of example 66c (0.5 g; 1.7 mmol) in methanol(13.6 ml) was stirred with 1N NaOH (3.4 ml; 3.4 mmol) at roomtemperature for 1 h. It was concentrated, treated with water extractedwith EtOAc. The aqueous layer was acidified with dil. HCl. The titlecompound precipitated as a white solid. It was filtered, washed withwater and dried. Yield, 0.45 g (95%); mp, 230-31° C.; MS (ESI″): 272(M−1), analysis: C₁₃H₁₁N₃O₄ requires C, 51.14; H, 4.06; N, 15.38. found:C, 51.10; H, 4.20; N, 14.90%.

Example 66e(4-{2-[5-(5-Methyl-[1,2,4]oxadiazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperazin-1-yl)-aceticacid ethyl ester

DCC (0.433 g; 2.1 mmol) was added with vigorous stirring to a solutionof the compound of example 66d (0.53 g; 1.9 mmol) and1-hydroxybenzotriazole (0.338 g; 2.47 mmol) in dry DMF (15 ml) at 0° C.After 10 min. piperazin-1-yl-acetic acid ethyl ester (0.43 g; 2.47 mmol)was added to the mixture It was stirred at 0° C. for 1 h and then keptin the freezer over night. The DCU was filtered off and the filtrate waswashed with 1N aqueous NaHCO₃, water, 1N aqueous HCl, brine, dried(Na₂SO₄), concentrated and purified using flash chromatography (silicagel, 5% MeOH in chloroform) to obtain the title compound. Yield, 0.64 g(77%); mp, 189-90° C.; MS (ESI⁺): 450 (M⁺+Na), analysis: C₂₁H₂₅N₅O₅requires C, 59.01; H, 5.90; N, 16.38. found: C, 58.80; H, 5.93; N,15.80%.

Example 67(1-{2S-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-hydroxy-phenyl)-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 67g in twosteps, using the procedures sequentially, described in examples 1i and4. It was purified using flash chromatography (silica gel, 3% MeOH inchloroform). Yield, 48%; mp, 116-18° C.; MS (ESI): 547 (M⁺+Na), 525.(M⁺+1), analysis: C₂₇H₃₂N₃O₇, 1.5H₂O requires: C, 58.74; H, 5.80; N,10.15. found: C, 58.60; H, 5.97; N, 10.00%.

Example 67a 4-Hydroxy-piperidine-1-carboxylic acid benzyl ester

Benzyl chloroformate (8.55 mL; 60 mmol) was added drop wise over aperiod of 30 min to a well stirred chilled mixture of piperidin-4-ol (5g; 49.44 mmol), 1N aqueous NaOH (60 mL; 60 mmol) and dioxane (60 mL).The mixture was stirred for 30 min. at room temperature, treated withwater, acidified with conc. HCl to pH 2 and extracted with EtOAc. TheEtOAc layer was washed with water, brine, dried (Na₂SO₄), concentratedand purified using flash chromatography (silica gel, 50% CH₂Cl₂ in PE60-80° C., 10% CH₃CN+2% MeOH in chloroform). Yield, 12.5 g (99%), oil;MS (CI): 236 (M⁺+1). 218, 192, 174, 91.

Example 67b 4-Ethoxycarbonylmethoxy-piperidine-1-carboxylic acid benzylester

The compound of example 67a (16 g; 70 mmol) in dioxane (25 ml) was addeddrop wise at 5-10° C. to (toluene washed) 55% NaH (3.84 g; 80 mmol)suspended in dioxane (25 ml) over a period of 30 min. in an atmosphereof nitrogen. The reaction mixture was stirred at room temperature for 1h, cooled to 0° C. and treated to a drop wise addition of ethyl2-bromoacetate (8.9 ml; 80 58 mmol) over a period of 15-20 min. It waspoured over crushed ice, and extracted with EtOAc. The EtOAc layer waswashed with brine, dried (Na₂SO₄), concentrated and purified using flashchromatography (silica gel, 5-10% CH₃CN in chloroform). Yield, 18.5 g(84.55%), oil; MS (ESI): 344 (M⁺+Na), 322 (M⁺+1).

Example 67c (Piperidin-4-yloxy)-acetic acid ethyl ester, hydrochloride

The compound of example 67b (14 g, 43.56 mmol) in MeOH (150 ml) and AcOH(10 ml) was hydrogenated using 10% Pd—C (0.15 g) at 40-50 psi for 4 h.The catalyst was filtered off and treated with ethereal HCl. It wasconcentrated and the title compound obtained was crystallized from dryMeOH in ether. Yield, 9.5 g (97.5%).

Example 67d(1-{2-Benzyloxycarbonylamino-3-[4-benzyloxycarbonyloxy-phenyl]-propionyl}-piperidine-4-yloxy)-aceticacid ethyl ester

DCC (4.12 g; 20 mmol) in EtOAc (10 ml) was added under vigorous stirringto a solution of di-Z-L-Tyr (8.08 g; 18 mmol) and HOBt (2.7 g; 20 mmol)in EtOAc (100 ml) at 0° C. After 10 min, the compound of example 67c(4.46 g; 19.93 mmol) was neutralized with Et₃N (2.8 ml; 20 mmol) in DMF(10 ml) at 0° C. and was added to the reaction mixture. The resultingmixture was stirred at 0° C. for 2 h and then kept in the freeze overnight (˜16 h). DCU was filtered off. The filtrate was successivelywashed with 1N NaHCO₃, water, 1N HCl and brine. It was dried overanhydrous Na₂SO₄. The solvent was removed. The crude product waspurified by flash chromatography with 10% CH₃CN in CHCl₃. Yield, 8.2 g(73.6%); MS (ESI): 641 (M⁺+Na), 619 (M⁺+1); analysis: C₃₄H₃₈N₂O₉requires: C, 66.01; H, 6.19; N, 4.53. found: C, 66.39; H, 6.58; N,4.81%.

Example 67e(1-{2-Amino-3-[4-hydroxy-phenyl]-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester, hydrochloride

The compound of example 67d in MeOH and AcOH was hydrogenated using 10%Pd—C for 2 h at 40-50 psi. The catalyst was filtered off and etherealHCl added. It was concentrated and the title compound obtained wascrystallized from dry MeOH in ether. Yield, 85%; MS (ESI): 373 (M⁺+Na),351 (M⁺+1).

Example 67f(1-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-hydroxy-phenyl)-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 67e usingthe procedure described in example 1g. It was purified using flashchromatography (silica gel, 10% CH₃CN, 2% MeOH in CHCl₃). Yield, 22%;mp, 73-75° C.; MS (CI): 520 (M⁺+29), 492. (M⁺+1), 292, 188, 158;analysis: C₂₇H₂₉N₃O₆ requires: C, 65.98; H, 5.95; N, 8.55. found: C,65.68; H, 5.94; N, 8.18%.

Example 67g(1-{3-[4-Hydroxy-phenyl]-2-(1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl)-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 67f usingthe procedure described in example 1h. It was purified using flashchromatography (silica gel, 10% CH₃CN and 1% MeOH in chloroform). Yield,95%; mp, 110° C.; MS (ESI): 548 (M⁺+Na), 526. (M⁺+1), 292, 188, 158.

Example 68(1-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 68d in twosteps, using the procedures sequentially, described in examples 1i and4. It was purified using flash chromatography (silica gel, 25% CH₃CN inchloroform, 2-5% MeOH in chloroform). Yield, 67%, white solid; mp,204-06° C. (MeOH: CHCl₃-PE 60-80° C.); MS (ESI): 441 (M⁺+Na), 419(M⁺+1); analysis: C₂₀H₂₆N₄O₆ requires: C, 57.41; H, 6.26; N, 13.39.found: C, 57.51; H, 6.60; N, 13.49%.

Example 68a(1-{2-tert-Butoxycarbonylamino-acetyl}-piperidin-4-yloxy)-acetic acidethyl ester

The title compound was obtained by reaction oftert-butoxycarbonylamino-acetic acid and Piperidin-4-yloxy)-acetic acidethyl ester, hydrochloride (67c), using mixed anhydride proceduredescribed for compound in example 25a. The crude product was purified byflash chromatography with 1% MeOH in chloroform. Yield, 84.6%, oil;analysis: C₁₆H₂₅N₂O₆ requires: C, 55.80; H, 8.19; N, 8.13. found: C,55.48; H, 8.28; N, 8.06%.

Example 68b (1-{2-Amino-acetyl}-piperidin-4-yloxy)-acetic acid ethylester, hydrochloride

The title compound was obtained from the compound of example 68a usingthe procedure described in example 5b. Yield, 98%; MS (ESI): 267(M⁺+Na), 245 (M⁺+1).

Example 68c(1-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 68b usingthe procedure described in example 1g. It was purified using flashchromatography (silica gel, 5% CH₃CN in chloroform, 2-5% MeOH inchloroform). Yield, 38.6%; mp, 109-11° C.; MS (ESI): 408 (M⁺+Na), 386(M⁺+1); analysis: C₂₀H₂₃N₃O₅ requires: C, 62.33; H, 6.01; N, 10.90.found: C, 62.74; H, 6.19; N, 10.99%.

Alternative Method for Example 68c:

(5-cyano-1-oxo-1,3-dihydro-isoindol-2-yl)-acetic acid: Compound ofexample 66a (3.0 g; 12.8 mmol) was dissolved in THF (47.3 ml) andhydrolyzed with 0.5M LiOH (27.7 ml) for 30 min. The pH of the reactionwas brought to 2 by adding 1N HCl. Most of the organic solvent wasremoved. The solid was filtered and washed with water. After dryingunder vacuum for 2 h at 50° C. it was crystallized from hot EtOAc-PE60-80° C. Yield, 2.56 g (91.8%); mp, 262° C.; MS (EI): 216 (M⁺), 171,115; analysis: C₁₁H₈N₂O₃ 0.25H₂O requires: C, 59.81; H, 3.86; N, 12.71.found: C, 60.17; H, 3.67; N, 13.06%.

(5-cyano-1-oxo-1,3-dihydro-isoindol-2-yl)-acetic acid: obtained abovewas reacted with (Piperidin-4-yloxy)-acetic acid ethyl ester,hydrochloride (67c) by mixed anhydride method as described for thepreparation of 25a to obtain 68c in 60% yield.

Example 68d(1-{2-[1-Oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 68c usingthe procedure described in example 1h. It was purified using flashchromatography (silica gel, 25% CH₃CN in chloroform). Yield, 81%, yellowsolid; mp, 177-80° C. (CHCl₃-PE 60-80° C.); MS (ESI): 442 (M⁺+Na), 420(M⁺+1); analysis: C₂₀H₂₅N₃O₅S requires: C, 57.26; H, 6.01; N, 10.02; S,7.64. found: C, 57.44; H, 6.24; N, 10.27; S, 7.96%.

Example 69(1-{3-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 69d in twosteps, using the procedures sequentially, described in examples 1i and4. It was purified using flash chromatography (silica gel, 25% CH₃CN inchloroform, by 2-5% MeOH in chloroform). Yield, 44%, white solid; mp,151-52° C.; MS (ESI): 455 (M⁺+Na), 433 (M⁺+1); analysis: C₂₁H₂₈N₄O₆,requires: C, 58.32; H, 6.53; N, 12.95. found: C, 57.92; H, 6.61; N,12.89%.

Example 69a(1-{3-tert-Butoxycarbonylamino-propionyl}-piperidin-4-yloxy)-acetic acidethyl ester

Treatment of Boc- □Ala with (Piperidin-4-yloxy)-acetic acid ethyl ester,hydrochloride (67c), by mixed anhydride procedure described for compoundin example 25a. The crude product was purified by flash chromatographywith 1% MeOH in chloroform. Yield, 70%, oil; MS (CI): 387 (M⁺+29), 359(M⁺+1), 259 (100%); analysis: C₁₇H₃₀N₂O₆ requires: C, 56.97; H, 8.44; N,7.82. found: C, 56.67; H, 8.56; N, 7.60%.

Example 69b (1-{3-Amino-propionyl}-piperidin-4-yloxy)-acetic acid ethylester, hydrochloride

The title compound was obtained from the compound of example 69a usingthe procedure described in example 5b; Yield, 98%; mp, 70° C.; MS (ESI):259 (M^(F)-1-1); analysis: C₁₂H₂₃ClN₂O₄ requires: C, 48.90; H, 7.86; N,9.50; Cl, 12.03. found: C, 48.93; H, 8.18; N, 9.61; Cl, 11.83%.

Example 69c(1-{3-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-propionyl}-piperidine-4-yloxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 69b usingthe procedure described in example 1g. It was purified using flashchromatography (silica gel, 5% CH₃CN in chloroform, 2-5% MeOH inchloroform). Yield, 35%; mp, 60° C.; MS (ESI): 422 (M⁺+Na), 400 (M⁺+1);analysis: C₂₁H₂₅N₃O₅, 0.5H₂O requires: C, 61.69; H, 6.12; N, 10.28.found: C, 62.06; H, 6.17; N, 10.62%.

Example 69d(1-{3-[1-Oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 69c usingthe procedure described in example 1h. It was purified using flashchromatography (silica gel, 5% CH₃CN in chloroform, 1% MeOH inchloroform). Yield, 98%, yellow solid; mp, 190° C.; MS (ESI): 456(M⁺+Na), 434 (M⁺+1); analysis: C₂₁H₂₇N₃O₅S requires: C, 58.18; H, 6.28;N, 7.69; S, 7.4. found: C, 58.61; H, 6.60; N, 9.76; S, 7.29%.

Example 70(1-{2-[5-(5-Methyl-isoxazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester

A solution of the compound of example 68 (1.3 g; 3.1 mmol) in aceticanhydride (22 ml) was heated at 120-30° C., following the reportedprocedure (J. Gante. et. al. Bioorg Med Chem. Lett. 1995, 6, 2425). Itwas purified using flash chromatography (silica gel, 2% MeOH in CHCl₃)and crystallized from chloroform-ether to obtain the title compound as awhite solid. Yield, 0.96 g (69%); rap, 126-27° C.; MS (ESI): 443 (M⁺+1);analysis: C₂₂H₂₆N₄O₆, requires: C, 59.72; H, 5.92; N, 12.66. found: C,59.18; H, 5.90; N, 12.30%.

Example 71(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester, acetic acid salt, sesquihydrate

The title compound was obtained from the compound of example 69d in twosteps, using the procedures sequentially, described in examples 1i and3. It was purified using, flash chromatography (RP-18 using 30% MeOH and0.2% AcOH in water) and triturated with MeOH-ether to obtain a whitesolid. Yield, 42%; mp, 189-90° C.; MS (ESI): 403 (M⁺+1); analysis:C₂₂H₃₀N₄O₇, 1.5H₂O requires: C, 53.93; H, 6.74; N, 11.44. found: C,53.73; H, 6.58; N, 11.67%.

Example 72(1-{2-[5-(tert-Butoxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-acetic acid ethyl ester,sesquihydrate

NaHCO₃ (0.326 g; 3.88 mmol) was added at 0° C. to a mixture of thecompound of example 71 (1.2 g; 2.59 mmol), dioxane (15 ml), water (7.5ml) and 1N aqueous NaOH (2.59 ml). Subsequentlydi-tert-butyl-dicarbonate (0.847 g; 3.88 mmol) in dioxane (2 ml) wasadded. The reaction mixture was stirred at room temperature for 1 h,stripped off dioxane and extracted with EtOAc. The EtOAc layer waswashed with water, dried (Na₂SO₄), concentrated and purified using flashchromatography (silica gel, 25% CH₃CN in chloroform, 2% MeOH inchloroform) to afford the title compound Yield, 0.75 g, white solid,(57%); mp, 83-85° C.; MS (ESI): 503 (M⁺+1); analysis: C₂₅H₃₄N₄O₇, 1.5H₂Orequires: C, 56.65; H, 6.99; N, 10.60. found: C, 56.52; H, 6.87; N,11.29%.

Example 73(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid, hydrochloride, trihydrate

Aqueous 1N NaOH (1.81 ml; 1.81 mmol) was added to a well-stirredsolution of the compound of example 72 (0.7 g; 1.39 mmol) in MeOH (7.2ml) at room temperature. The reaction mixture was allowed to furtherstir at room temperature for 1 h. Methanol was removed under reduced andthe aqueous layer was acidified with dil HCl at 0° C. The reactionmixture was evaporated to dryness. The crude material obtained wasdissolved in a solution of 5% MeOH in chloroform (30 ml) and filtered.The filtrate was taken to dryness and the residue was triturated withdry ether to afford the title compound as a pure white solid. Yield,14%, white solid; mp, 135-36° C.; MS (ESI): 373 (M⁺−1); analysis:C₁₈H₂₃ClN₄O₅, 3H₂O requires: C, 46.50; H, 6.29; Cl, 7.63; N, 12.05.found: C, 46.63; H, 6.23; Cl, 7.43; N, 11.64%.

Example 74(4-{2-[5-Acetimidoylamino-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester; hydro iodide, hemi hydrate

The title compound was prepared by refluxing a mixture of 74b, 74c andNaHCO₃ in acetonitrile for 4 h. It was concentrated and purified usingflash chromatography (silica gel, 10% CH₃CN and 3% MeOH in chloroform)and triturated with MeOH-ether containing a few drops of EtOAc to obtaina pure white solid. Yield, 26%; mp, 196-97° C.; MS (ESI): 426 (M⁺+1);analysis: C₂₂H₂₄IN₃O₆, 0.5H₂O, requires: C, 46.94; H, 4.95; N, 7.47.found: C, 46.56; H, 4.54; N, 7.32%.

Example 74a(3-Hydroxy-4-{2-[5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 41d andethyl 2-bromomethyl-4-nitrobenzoate using the procedure described inexample 1g. It was purified using flash chromatography (silica gel, 5%CH₃CN in chloroform) and crystallized from CHCl₃-EtOAc-PE 60-80° C.Yield, 16%, off white solid; mp, 224-26° C.; MS (ESI): 437 (M⁺+Na), 415(M⁺+1); analysis: C₂₀H₁₈N₂O₈ requires: C, 57.97; H, 4.38; N, 6.76.found: C, 58.23; H, 4.38; N, 6.64%.

Example 74b(4-{2-[5-Amino-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester

A mixture of the compound of example 74a, cobalt (II) chloride and Znpowder in DMF and water was stirred to obtain the title compound,according to reported procedure (see Ind. J. Chem. 33B, 758, 1994). Itwas purified using flash chromatography (silica gel, 10% CH₃CN and 0.5%MeOH in chloroform) and crystallized using CHCl₃-PE 60-80° C. Yield,43%, white solid; mp, 193-94° C.; MS (ESI): 407 (M⁺+Na), 385 (M⁺+1);analysis: C₂₀H₂₀N₂O₆ requires: C, 62.49; H, 5.24; N, 7.29. found: C,62.95; H, 5.42; N, 7.31%.

Example 74c Thioacetimidic acid methyl ester hydroiodide

The title compound was obtained from thioacetamide using the proceduredescribed in example 1i as a white solid white solid. Yield, 72%; mp,158-60° C.; MS (EI): 89 (M⁺); ¹H NMR (DMSO-D₆): 2.56 (3H, s, CH ₃), 2.71(3H, s, SCH ₃), 11.6 (1H, br, NH).

Example 75(3-Ethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was Obtained from the compound of example 75c usingthe procedure described in example 4. It was purified using flashchromatography (silica gel, 2% MeOH in chloroform). Yield, 50%, whitesolid; mp, 192-94° C.; MS (ESI): 478.55 (M⁺+Na), 456.37 (M⁺+1);analysis: C₂₃H₂₅N₃O₇, requires C, 60.65; H, 5.53; N, 9.23. found: C,60.57; H, 5.42; N, 8.73%.

Example 75a(4-{2-[5-Cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy-phenoxy)-aceticacid ethyl ester

Ethyl bromide (0.662 ml; 8.87 mmol) was added to a mixture of thecompound of example 41f (0.7 g; 1.77 mmol), anhydrous K₂CO₃ (1.23 g;8.87 mmol) and KF (0.07 g) in DMF (60 ml), with stirring at roomtemperature. The reaction mixture was stirred at room temperature for 16h, poured over ice containing dill. HCl and extracted with EtOAc. TheEtOAc layer was washed with water, dried (Na₂SO₄.), concentrated andpurified using flash chromatography (silica gel, 5% CH₃CN inchloroform). Yield, 0.585 g (78%); white solid; mp, 180-81° C. (CHCl₃-PE60-80° C.); MS (ESI): 445 (M⁺+Na), 423 (M⁺+1-1); analysis: C₂₃H₂₂N₂O₆,requires C, 65.40; H, 5.25; N, 6.63. found: C, 65.75; H, 5.07; N, 6.11%.

Example 75b(3-Ethoxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 75a usingthe procedure described in example 1h. It was purified using flashchromatography (silica gel, 2% MeOH in chloroform). Yield, 95%, yellowsolid; mp, 176-77° C.; MS (ESI): 480 (M⁺+Na), 458 (M⁺+1); analysis:C₂₃H₂₄N₂O₆S, requires C, 60.51; H, 5.30; N, 6.14; S, 7.02. found: C,60.17; H, 5.36; N, 5.66; S, 7.39%.

Example 75c(3-Ethoxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 75b usingthe procedure described in example 11. Yield, 98%, yellow solid; mp,169-72° C.; MS (ESI): 471.5 (M⁺+1),

Example 76(4-{2-[5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 75c usingthe procedure described in example 1. It was purified using flashchromatography (RP-18 with 40% MeOH and 2% AcOH in water) andcrystallized using MeOH-ether. Yield, 0.44 g (59%); mp, 202-03° C.; MS(ESI⁺): 440.54 (M⁺+1); analysis: C₂₅H₂₉N₃O₈, requires C, 60.11; H, 5.85;N, 8.41. found: C, 59.87; H, 5.87; N, 8.33%.

Example 77(4-{2-[5-Carbamimdoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy-phenoxy)-aceticacid, hydrochloride, hemihydrate

Aqueous 1N NaOH (1.6 ml; 1.6 mmol) was added to a well stirred mixtureof the compound of example 76 (0.4 g; 0.8 mmol) and NaHCO₃ (0.1 g; 1.2mmol) in dioxane-water (1:1; 5 ml) at 0° C. Subsequentlydi-tert-butyldicarbonate (0.262 g; 1.2 mmol) in dioxane (2.5 ml) wasadded. The reaction mixture was gradually brought to room temperature,and then allowed to stir for another 1 h. Dioxane was removed underreduced pressure. The residue was treated with water and extracted withEtOAc. The aqueous layer was acidified with 6N HCl to pH 3 and kept atroom temperature for 16 h. The white solid that separated was filtered,washed with water, MeOH, ethyl acetate and dried to afford the puretitle compound. Yield, 0.126 g (35%); mp, 241-42° C.; MS (ESI⁺): 413.61(M⁺+1); analysis: C₂₁H_(n)ClN₃O₆, 0.5H₂O; requires C, 55.16; H, 5.03; N,9.19. found: C, 55.16; H, 5.43; N, 9.22%.

Example 78(3-Hydroxy-4-{2-[1-oxo-5-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

A mixture of the compound of example 42 (0.3 g; 0.7 mmol) and1,1′-carbonyldiimidazol (0.17 g; 1.05 mmol) in DMF (10 ml) was stirredat room temperature for 12 h. The reaction mixture was diluted withwater (100 ml) and extracted with EtOAc. The EtOAc layer was washed with1N HCl, water, brine, dried (Na₂SO₄), concentrated, purified using flashchromatography (silica gel, 5% MeOH in chloroform) and crystallized fromMeOH-ether to obtain the title compound. Yield, 0.032 g; (10%), whitesolid; mp, 223-25° C.; MS (ESI): 452.59 (M−1), analysis: C₂₂H₁₉N₃O₈,requires C, 57.09; H, 4.32; N, 9.08. found: C, 57.74; H, 4.18; N, 8.93%.

Example 79(4-{2-[5-(Acetylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester

A mixture of the compound of example 42 (0.5 g; 1.17 mmol), KF (0.05 g),pyridine (0.189 ml; 2.34 mmol) and acetyl chloride (0.167 ml; 2.34 mmol)in DMF (10 ml) was stirred at room temperature for 3 h. The reactionmixture was diluted with ice water (100 ml) and extracted withdichloromethane. The organic layer was washed with water, brine, dried,(Na₂SO₄) and concentrated to obtain the crude product, which waspurified by triturating with MeOH, CHCl₃ and ether to obtain the titlecompound as a pure white solid. Yield, 0.414 g; (75%); mp, 196-98° C.;MS (ESI⁺): 470.61 (M⁺+1), analysis: C₂₃H₂₃N₃O₈, requires C, 58.85; H,4.94; N, 8.95. found: C, 58.47; H, 4.44; N, 8.48%.

Example 80(3-Acetoxy-4-{2-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 42 usingthe procedure described in example 79 with the exception of using 8equivalent of acetyl chloride and three times the amount of KF usedearlier. Yield, 26%; mp, 162-64° C.; MS (ESI⁺): 494 (M⁺+1); analysis:C₂₅H₂₃N₃O₈, requires C, 59.70; H, 4.78; N, 8.36. found: C, 60.08; H,4.11; N, 7.85%.

Example 81(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid ethyl ester, acetic acid salt, hemi hydrate

A mixture of the compound of example 58 (0.15 g; 0.319 mmol), glacialacetic acid (20 ml) and Ac₂O (0.066 ml; 0.703 mmol) was stirred at roomtemperature for 10 min. The mixture was filtered and the filtrate washydrogenated using 10% Pd—C (0.02 g) at 20 psi for 15 min. The catalystwas filtered off and the filtrate was evaporated to dryness. The crudeproduct was purified using flash chromatography (silica gel, 40% MeOHand 0.2% AcOH in water). The pure product was crystallized usingMeOH-ether. Yield, 0.105 g (64%); mp, 186-88° C.; analysis: C₂₆H₃₁N₃O₈0.5H₂O, requires C, 59.71; H, 6.12; N, 8.04. found: C, 59.53; H, 5.94;N, 7.45%.

Example 82(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-acetic acid, sesquihydrate

NaOH (0.038 g; 0.937 mmol) in absolute EtOH (1 ml) was added to asuspension of the compound of example 58 (0.1 g; 0.0.213 mmol) inabsolute EtOH (5 ml), and the clear solution was stirred at roomtemperature till the starting material was consumed. It was concentratedtreated dil. HCl. and evaporated to dryness. The crude material waspurified using flash chromatography (RP-18 with 1:1 MeOH: 0.2% AcOH inwater). Triturating with ether and a trace amount of methanol purifiedthe residue. Yield, 0.35 g (37%), white solid; analysis: C₂₂H₂₃N₃O₇1.5H₂O, requires C, 56.35; H, 5.55; N, 8.97. found: C, 56.77; H, 4.98;N, 8.92%.

Example 83(3-Allyloxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester, hemihydrate

The title compound was obtained from the compound of example 83c usingthe procedure described in example 4. It was purified using flashchromatography (silica gel, 4% CH₃CN in chloroform, 2% MeOH inchloroform). Yield, 77%, white solid; mp, 182-83° C.; analysis:C₂₄H₂₅N₃O₇, 0.5H₂O, requires C, 60.49; H, 5.46; N, 8.81. found: C,60.22; H, 5.09; N, 8.59%.

Example 83a(3-Allyloxy-4-{2-[5-cyano-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester

The title compound was obtained from the compound of example 41f usingthe procedure described in example 75a. It was purified using flashchromatography (silica gel, 5-10% CH₃CN in chloroform). Yield, 76%,white solid; mp, 126-28° C. (CHCl₃-PE 60-80° C.); MS (ESI): 457.523(M⁺+Na), 435.5 (M⁺+1); analysis: C₂₄H₂₂N₂O₆, requires C, 66.35; H, 5.10;N, 6.45. found: C, 66.14; H, 5.81; N, 6.97%.

Example 83b(3-Allyloxy-4-{2-[1-oxo-5-thiocarbamoyl-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester, hemihydrate

The title compound was obtained from the compound of example 83a usingthe procedure described in example 1h. It was purified by flashchromatography (silica gel, 5% CH₃CN in chloroform, 2% MeOH inchloroform). Yield, 76%, yellow solid; mp, 74-76° C.; analysis:C₂₄H₂₄N₂O₆S, 0.5H₂O, requires C, 60.31; H, 5.24; N, 5.86; S, 6.70.found: C, 60.58; H, 4.97; N, 5.83; S, 7.03%.

Example 83c(3-Allyloxy-4-{2-[5-methylsulfanylcarbonimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester, hydroiodide

The title compound was obtained from the compound of example 83b usingthe procedure described in example 11. Yield, 98%, yellow solid; mp,130° C. (d); MS (CI): 512 (M⁺+29), 484 (M⁺+1); analysis: C₂₅H₂₇IN₂O₆S,requires C, 49.29; H, 4.15; N, 4.02; I, 20.18; S, 5.38. found: C, 49.19;H, 4.46; N, 4.49; I, 20.49; S, 5.25%.

The efficacy of the present compounds in antagonizing the activity ofthe fibrinogen receptor can be determined by a number of pharmacologicalassays well known in the art, such as described below. The exemplifiedpharmacological assays, which follow herein below, have been carried outwith the compounds of the present invention and their salts.

In vitro Biological Experiments

Human blood (150 ml) was collected from the ante-cubital vein of normalhealthy volunteers (who were not on any medication for the past twoweeks), into a siliconized glass bottle containing 25 ml ofacid-citrate-dextrose (ACD) solution and 10 units of hirudin. The bloodwas immediately centrifuged at 200×g for 20 min at room temperature.Platelet-rich plasma (PRP) was separated and the platelet count readusing a Beckman Coulter A^(c)T diff Counter. The tubes were centrifugedagain at 2000×g for 10 min at room temperature, to get platelet-freeplasma (PFP). The platelet count of PRP was adjusted to 3×10⁸platelets/ml by appropriate dilution with PFP. All in vitro experimentswere conducted using PRP with adjusted number of platelets.

Inhibition of Platelet Aggregation in Human PRP (Born, G. V. R.; Cross,M. J., J. Physiol, 1963, 168, 175)

PRP was incubated with different concentrations of the test compound for3 min at 37° C. Platelet aggregation was then induced by the addition ofADP (5-15 μM final concentration). Percent inhibition of plateletaggregation was then calculated by comparing test aggregation valueswith control values (Table 1).

TABLE 1 Example No. IC₅₀ (μM) 3 0.093 20 0.05 24 0.006Inhibition of Aggregation of Gel-Filtered Platelets (GFP) (Charo, I. F.,Nanizzi, L. et al, J. Biol. Chem, 1991, 266, 1415-1421) (Table 2).

TABLE 2 GFP Study % Inhib. against Example No ADP Thromb. 3 0.74 0.45 200.62 0.39

PRP was centrifuged at 285×g for 20 min to pellet the platelets. Theplatelet pellet was resuspended in Tyrode's buffer containing hirudin(0.06 unit/ml) and apyrase (40 mcg/ml). The platelet suspension waslayered on to a Sepharose 2B (Sigma) column, previously equilibratedwith Tyrode buffer (pH 7.4). Elution of platelets was carried out withTyrode buffer containing dextrose (5.5 mM) and BSA (0.35%). The count ofGFP was adjusted to 3×10⁸ platelets/ml with Tyrode's buffer. GFPsuspension was mixed with ADP and fibrinogen and aggregation ofplatelets was studied in presence and in absence of the test compound.Similarly, the effect of the test compound on thrombin-induced plateletaggregation was studied.

Receptor Binding Assay: (Mousa S. A., et al. Cardiology.1993:83:374-382. and Charo, I. F., Nanizzi, L. et al, J. Biol. Chem.,1991, 266, 1415-1421)

Biotinylation of Fibrinogen

Fibrinogen was dialyzed against 0.1 M NaHCO₃, 0.1 M NaCl, pH 8.2 andspun in an ultracentrifuge at 1,00000×g for 30 minutes at 4° C. toremove any particulate matter. The protein concentration was adjusted to1 mg/ml. Solid sulfo-N-hydroxy-succinimido-biotin (0.2 mg of biotinester/ml of adhesive protein) was added and gently mixed end-over-endfor 30 minutes at room temperature. The unreacted biotin ester wasremoved by exhaustive dialysis against 50 mM Tris.HCl, 100 mM NaCl,0.05% NaN₃, pH −7.4 at 4° C. The biotinylated fibrinogen is stored at 4°C. until use.

Method

The GP IIb/IIIa protein (1 mg/ml) was diluted 1:200 with a TritonX-100-free buffer containing 20 mM Tris-HCl, 150 mM NaCl, 1 mM CaCl₂,0.02% NaN₃ (Buffer A). This protein was immediately added to 96-wellmicrotiter plates (Immulon II—Dynatech) at 0.1 ml (0.5 mg) per well andincubated overnight at 4° C. The wells were washed once with 50 mM Tris,100 mM NaCl, 2 mM CaCl₂, 0.02% NaN₃, pH 7.4 (buffer B). The unboundsites were then blocked by incubating the wells with 0.1 ml solutionbuffer B containing 35 mg/ml BSA, for 2 hours at 30° C. The wells werewashed again with buffer B containing 1 mg/ml BSA (incubation buffer).The fibrinogen receptor antagonists were added simultaneously withbiotinylated fibrinogen, so as to induce competition for binding to thegpIIb/IIIa receptor. Biotinylated fibrinogen (0.1 ml/well) was added ata final concentration of 10 nM and incubated for 3 hours at 30° C. Afterincubation, the wells were aspirated completely and washed once with 250μl of binding buffer. Bound fibrinogen was quantitated by addition of0.1 ml of Streptavidin horseradish peroxidase (1:2000 dilution). Thewells were then washed with incubation buffer and 100 μl of thesubstrate 3,3′,5,5′-tetramethyl-benzidine dihydrochloride was added.(The substrate was prepared daily following the manufacturer'sinstructions—1 mg/ml of substrate prepared in DMSO was added to 9 ml ofcitrate buffer, pH=4). The kinetics of colour development was followedat 450 nm (Ref filter—630 nm) using a microtiter plate reader.

Ex Vivo Biological Experiments

Mouse Ex Vivo Studies: (Weller, T., Alig, L., et al J. Med. Chem., 1996,39, 3139-3147)

Mice of either sex weighing between 25-35 g were orally fed the testcompound. Blood was collected, from the abdominal aorta into ACDsolution, at different time-points ranging from 15 min to 6 h. The bloodsamples were centrifuged at 2000×g for 10 min to get PFP. This plasmawas separated and used as test sample to study its effect on ADP-inducedhuman platelet aggregation (Table 3).

TABLE 3 Ex vivo in mice (1 mg/kg, p.o) Activity Example Peak activity(%) at Last time point * Activity (%) at No. (time in hours) peak (timein hours) last time point 42 0.75 100 6 62 49 0.75 65 3 38 23 1 100 435 * Time point after which the activity fell below 30%

Guinea Pig Ex Vivo Studies:

Guinea pigs of either sex weighing between 500-800 g were orally fed thetest compound. Blood was collected, from the carotid artery into ACDsolution, at different time-points ranging from 1 to 24 h. PRP wasseparated and the platelet count adjusted to 3×10⁸ platelets/ml usingPFP. The effect of the test compound on ADP-induced guinea pig plateletaggregation was studied (Table 4).

TABLE 4 Ex vivo in Guinea pigs (3.1 mg/kg, p.o) Activity Example Peakactivity (%) at Last time point * Activity (%) at No. (time in hours)peak (time in hours) last time point 42 7 100 15 78 23 7 100 13 48 *Time point after which the activity fell below 30%

In Vivo Biological Experiments

Thrombocytopenia in Guinea Pigs: (Voelkl K-P., Dierichs, R. Thromb. Res.1986, 42, 11-20)

Guinea pigs weighing between 500-800 g were orally fed the testcompound. After a fixed time interval the guinea pigs were anaethesizedand the carotid artery and jugular vein were cannulated. Blood sampleswere collected from the carotid artery. After collection of the controlblood sample (0 min), collagenase (10 mg/kg) was administered throughthe jugular vein. The endothelium gets damaged by the action ofcollagenase and causes platelets to aggregate at this site, therebyinducing thrombocytopenia. At every minute thereafter till 10 min and at15, 20, 25 and 30 min after the administration of collagenase, bloodsamples were collected. The platelet count was read using the BeckmanCoulter A^(c)T diff Counter. All counts were compared with the 0 min(before administration of proaggregatory challenge) sample to determinethe fall in the number of free circulating platelets. A graph of thenumber of platelets against time was plotted and the Area Under theCurve (AUC) was calculated for each animal. Percent protection wasdetermined by comparing the AUCs of treated to control animals.

Thrombus Formation in Hamster:

Hamsters weighing between 150-180 g were orally fed the test compound.After a fixed time interval they were anaesthetized and the abdominalaorta exposed. A copper wire with a one-centimeter long coil wasinserted through the abdominal aorta, all the way up to the thoracicaorta. After 10 min the copper wire was withdrawn and the size of thethrombus, formed on the wire, determined by estimating the proteincontent. Percent inhibition of thrombus formation was determined bycomparing the thrombi formed in the drug-treated group with those in thecontrol group.

The compounds of the present invention have an IC₅₀ below 100 nM, forADP-induced human platelet aggregation and ˜200 pM for fibrinogenbinding. Efficacy studies in guinea pigs revealed that the compoundsshow a long duration of action. The compounds of the present inventionalso inhibited collagenase-induced thrombocytopenia in guinea pigs.Toxicity studies with some of these molecules revealed that the LD50was >1000 mg/kg, p.o., in mice and rats. They did not significantlyincrease the bleeding time in guinea pigs.

1. A method of inhibiting binding of fibrinogen to blood platelets in asubject in need thereof, which comprises administering to the subject atherapeutically effective amount of a compound of the formula (I) or astereoisomer, a tautomer or a pharmaceutically acceptable salt thereof;

wherein ring A is phenyl; R^(A) is a group of formula (3):

wherein p is 0; s is 1; R¹ is selected from: H, hydroxy, alkyl,partially or fully fluorinated alkyl, alkoxy, alkenyl, alkynyl, carboxy,—C(═O)OR⁵, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle;R³ and R⁴ are independently selected from: H, alkyl, partially or fullyfluorinated alkyl, alkenyl, alkynyl, —C(═O)OR⁵, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycle, —OR⁵—SR⁵, —NR⁵R⁶,—S(═O)₂NR⁵R⁶, —S(═O)₂R⁵, —C(═O)R⁵, —C(═O)NR⁵R⁶, —C(═O)OR⁵, —C(═O)SR⁵,—OC(═O)R⁵, —OC(═O)OR⁵, —OC(═O)NR⁵R⁶, —OS(═O)₂R⁵, —S(C═O)NR⁵ and—OS(═O)₂NR⁵R⁶, or R³ and R¹ or R⁴, together with the respective nitrogenatoms to which they are attached, form an unsubstituted or substituted5-, 6- or 7-membered partially saturated or aromatic heterocycle,optionally having one or more additional heteroatoms selected from: N, Oand S, wherein the substituents are selected from: hydroxy, halogen,alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy and —C(═O)OR⁵; R⁵ and R⁶are independently selected from: H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl and heterocycle, wherein each of saidalkyl, alkenyl, alkynyl, cycloalkyl and cycloalkylalkyl group optionallycontains at least one hetero atom selected from: N, S and O anywhere inthe chain, including the terminal position; R^(B) is H; Y¹ and Y²,together, are selected from: ═O and ═S; Z is N; W is CH; R^(C) is H; nis 0, 1, 2 or 3; R^(D) and R^(E) are independently selected from: H andan unsubstituted or substituted group selected from: alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle,wherein the substituents are selected from: hydroxy, halogen, alkyl,alkenyl, alkynyl, oxo, carboxy, —C(═O)OR⁵, —OR¹⁷, —SR¹⁷, —NR¹⁷R¹⁸,—NHC(═O)R¹⁷, —NHC(═O)OR¹⁷, —OC(═O)R¹⁷, —SC(═O)R¹⁷, —OS(═O)₂R¹⁷ and—NHS(═O)₂R¹⁷; R¹⁷ and R¹⁸ have the same meaning as R⁵ and R⁶, definedabove; R^(F) is selected from: O, S and N(OR¹⁹); R¹⁹ has the samemeaning as R⁵, defined above; R^(G) is selected from: aryl, heteroaryl,and partially or fully saturated heterocycle, where said aryl,heteroaryl and heterocycle are substituted by one or more groups of theformula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) and optionally, further substituted byone or more groups selected from: —R⁵, halogen, —CN, —SCN, —CNO, —OR²¹,—OC(═O)R²¹, —OS(═O)₂R²¹, —OS(═O)₂NR²¹R²², —OC(═O)OR²¹, —OC(═O)SR²¹,—OC(═O)NR²¹R²², —SR²¹, —S(═O)R²¹, —NO₂, —NR²¹ (OR²²), —NR²¹R²²,—NR²¹C(═O)R²², —N(R²¹)C(═O)OR²², —N[S(═O)₂R²¹]R²³, C(═O)OR²¹, —S(═O)₂R²¹and —S(═O)₂OR²¹; R²¹ has the same meaning as R¹, defined above, and R²is selected from: H, hydroxy, alkyl, partially or fully fluorinatedalkyl, alkoxy, alkenyl, alkynyl, carboxy, —C(═O)OR⁵, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl and heterocycle: T is selected from:—CH₂, O, S and NH; q is 0, 1, 2 or 3; R²³ and R²⁴ are independentlyselected from: H, alkyl alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heterocycle and C(═O)R²⁵, wherein said alkyl andalkenyl optionally contain at least one hetero atom selected from: O, Sand N, in any position of the alkyl or alkenyl chain, and said alkyl andalkenyl are unsubstituted or substituted with at least one groupselected from: —OR¹, —OC(═O)R¹, —OS(═O)₂R¹, —S(═O)₂NR¹R², —OC(═O)OR¹,—OC(═O)SR¹, —OC(═O)NR¹R², —SR¹, —S(═O)R¹, —SC(═O)H, —SC(═O)OR¹,—NR¹(OR²), —NR¹R², —NR¹C(═O)R², —N(R¹)C(═O)OR², —NR¹S(═O)₂R², C(═O)OR¹,—S(═O)₂R¹ and —S(═O)₂OR¹; R²⁵ is selected from: OR⁵, SR⁵, —OCR³R⁴ and—NR⁵R⁶, wherein R³, R⁴, R⁵ and R⁶ are as defined above and whereinoptionally, R³ and R⁴, together with the carbon to which they areattached, form an unsubstituted or substituted 5-, 6- or 7-memberedsaturated, partially saturated or aromatic heterocycle having one ormore heteroatoms selected from: N, O and S, wherein the substituents areselected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo,carboxy and —C(═O)OR⁵; and the group NR⁵R⁶ is, optionally, a heterocyclecontaining at least one additional heteroatom selected from: O, S, andN.
 2. The method according to claim 1, wherein in the compounds offormula (I), R^(G) is selected from: phenyl, piperidinyl andpiperazinyl, and said phenyl, piperidinyl and piperazinyl aresubstituted by one or more groups of the formula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) and optionally, further substituted byone or more groups selected from: —R⁵, halogen, —CN, —SCN, —CNO, —OR²¹,—OC(═O)R²¹, —OS(═O)₂R²¹, —OS(═O)₂NR²¹R²², —OC(═O)OR²¹, —OC(═O)SR²¹,—OC(═O)NR²¹R²², —SR²¹, —NO₂, —NR²¹(OR²²), —NR²¹R²², —NR²¹C(═O)R²²,—N(R²¹)C(═O)OR²², —N[S(═O)₂R²¹]R²³, C(═O)OR²¹, —S(═O)₂R²¹ and—S(═O)₂OR²¹; and R²¹ and R²² are as defined in claim
 45. 3. The methodaccording to claim 1, wherein in the compounds of formula (I), R₁ ishydrogen; R₃ and R₄ are independently selected from: H, OH, —C(O)OH and—C(O)Oalkyl; R^(B)═R^(C)═R^(D)═R^(E)=hydrogen; Y¹ and Y², together are═O; n is the integer 0 or 1; R^(G) is phenyl, substituted with one ormore of the group of formula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) wherein R²³ is H and R²⁴ is H, and,optionally, the compound is further substituted with one or more of thegroups selected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl,oxo, carboxy, —C(═O)OR⁵, SR²¹, S(═O)₂R²¹ and —N(R²¹)—C(O)CH₃,—CH₂C(O)R²⁵; and R²⁵ is selected from: OR⁵, OCR³R⁴ and NR⁵R⁶, wherein R³and R⁴, together with the carbon to which they are attached form anunsubstituted or substituted 5-, 6- or 7-membered saturated, partiallysaturated or aromatic heterocycle having one or more heteroatomsselected from: N, O and S, wherein the substituents are selected from:hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy,—C(═O)OR⁵; and R⁵, R⁶ and R²¹ are independently selected from: H, alkyland phenyl.
 4. The method according to claim 1, wherein in the compoundsof formula (I) R₁ is hydrogen; R₃ and R₄ are independently selectedfrom: H, OH, —C(O)OH and —C(O)Oalkyl; R^(B)═R^(C)═R^(D)═R^(E)=hydrogen;Y¹ and Y², together are ═O; n is the integer 0 or 1; R^(G) is selectedfrom: piperidinyl and piperazinyl, wherein said piperidinyl andpiperazinyl are substituted with one or more of the group of formula(5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) wherein R²³ is H and R²⁴ is H and,optionally, further substituted with one or more groups selected from:hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy and—C(═O)OR⁵; and R²⁵ is OR⁵, wherein R⁵ is selected from: H, alkyl andphenyl.
 5. The method according to claim 1, wherein the compounds offormula (I) are selected from the group consisting of:(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;4-(2-{5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl}-acetyl]-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methanesulfonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethoxycarbonyl methoxy-phenoxy)-acetic acid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(imino-{3-methyl-butyrylamino}-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-1-hydroxyimino-ethyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isobutoxycarbonyl methoxy-phenoxy)-acetic acid isobutyl ester;2-(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-N,N-diethyl-acetamide;4-(2-{4-[2-(5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylicacid benzyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenylsulfanyl)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-chloro-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethylsulfanyl-phenoxy)-acetic acid ethyl ester;(2-Ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethanesulfonyl-phenoxy)-acetic acid ethyl ester;(2-Ethanesulfonyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2,6-Bis-ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Acetylamino-4-{2-[5-N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-methoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-propoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxycarbonylmethoxy-phenoxy)-acetic acid ethyl ester;(3-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(2-Ethylsulfanyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(5-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isopropyl-phenoxy)-aceticacid ethyl ester;(2-tert-Butyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid benzyl ester;(2-Ethyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid;(4-Hydroxy-3-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-5-methoxy-phenoxy)-aceticacid ethyl ester;(3,5-Dihydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceicacid ethyl ester;(2-Ethoxycarbonylmethoxy-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(1-{2S-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-hydroxy-phenyl)-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{3-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(5-Methyl-isoxazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(tert-Butoxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]acetyl}-piperidin-4-yloxy)-aceticacid;(3-Ethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-[2-(5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-3-ethoxy-phenoxy}-aceticacid ethyl ester;(4-{2-[5-Carbamimdoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy-phenoxy)-aceticacid;(3-Hydroxy-4-{2-[1-oxo-5-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-1,3-dihydro-isoindol-2-yl]acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(Acetylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Acetoxy-4-{2-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid; and(3-Allyloxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester.
 6. The method according to claim 3, wherein thecompounds of formula (I) are selected from the group consisting of(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;4-(2-{5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl}-acetyl]-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methanesulfonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethoxycarbonyl methoxy-phenoxy)-acetic acid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(imino-{3-methyl-butyrylamino}-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-1-hydroxyimino-ethyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isobutoxycarbonyl methoxy-phenoxy)-acetic acid isobutyl ester;2-(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-N,N-diethyl-acetamide;4-(2-{4-[2-(5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylicacid benzyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenylsulfanyl)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-chloro-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethylsulfanyl-phenoxy)-acetic acid ethyl ester;(2-Ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethanesulfonyl-phenoxy)-acetic acid ethyl ester;(2-Ethanesulfonyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2,6-Bis-ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Acetylamino-4-{2-[5-N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-methoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-propoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxycarbonylmethoxy-phenoxy)-acetic acid ethyl ester;(3-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(2-Ethylsulfanyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(5-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isopropyl-phenoxy)-aceticacid ethyl ester;(2-tert-Butyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid benzyl ester;(2-Ethyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid;(4-Hydroxy-3-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-5-methoxy-phenoxy)-aceticacid ethyl ester;(3,5-Dihydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceicacid ethyl ester;(2-Ethoxycarbonylmethoxy-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Ethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-[2-(5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-3-ethoxy-phenoxy}-aceticacid ethyl ester;(4-{2-[5-Carbamimdoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy-phenoxy)-aceticacid;(3-Hydroxy-4-{2-[1-oxo-5-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(Acetylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Acetoxy-4-{2-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid; and(3-Allyloxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester.
 7. The method according to claim 4, wherein thecompounds of formula (I) are selected from the group consisting of:(1-{2S-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-hydroxy-phenyl)-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{3-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(5-Methyl-isoxazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(tert-Butoxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester; and(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid.
 8. A method for the treatment of cardiovascular andcerebrovascular thromboembolic diseases in a subject in need thereof,which comprises administering to the subject a therapeutically effectiveamount of the compound of formula (I); or a stereoisomer, a tautomer ora pharmaceutically acceptable salt thereof;

wherein ring A is phenyl; R^(A) is a group of formula (3):

wherein p is 0; s is 1; R¹ is selected from: H, hydroxy, alkyl,partially or fully fluorinated alkyl, alkoxy, alkenyl, alkynyl, carboxy,—C(═O)OR⁵, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle;R³ and R⁴ are independently selected from: H, alkyl, partially or fullyfluorinated alkyl, alkenyl, alkynyl, —C(═O)OR⁵, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycle, —OR⁵, —SR⁵, —NR⁵R⁶,—S(═O)₂NR⁵R⁶, —S(═O)₂R⁵, —C(═O)R⁵, —C(═O)NR⁵R⁶, —C(═O)OR⁵, —C(═O)SR⁵,—OC(═O)R⁵, —OC(═O)OR⁵, —OC(═O)NR⁵R⁶, —OS(═O)₂R⁵, —S(C═O)NR⁵ and—OS(═O)₂NR⁵R⁶, or R³ and R¹ or R⁴, together with the respective nitrogenatoms to which they are attached, form an unsubstituted or substituted5-, 6- or 7-membered partially saturated or aromatic heterocycle,optionally having one or more additional heteroatoms selected from: N, Oand S, wherein the substituents are selected from: hydroxy, halogen,alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy and —C(═O)OR⁵; R⁵ and R⁶are independently selected from: H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl and heterocycle, wherein each of saidalkyl, alkenyl, alkynyl, cycloalkyl and cycloalkylalkyl group optionallycontains at least one hetero atom selected from: N, S and O anywhere inthe chain, including the terminal position; R^(B) is H; Y¹ and Y²,together, are selected from: ═O and ═S; Z is N; W is CH; R^(C) is H; nis 0, 1, 2 or 3; R^(D) and R^(E) are independently selected from: H andan unsubstituted or substituted group selected from: alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle,wherein the substituents are selected from: hydroxy, halogen, alkyl,alkenyl, alkynyl, oxo, carboxy, —C(═O)OR⁵, —OR¹⁷, —SR¹⁷, —NR¹⁷R¹⁸,—NHC(═O)R¹⁷, —NHC(═O)OR¹⁷, —OC(═O)R¹⁷, —SC(═O)R¹⁷, —OS(═O)₂R¹⁷ and—NHS(═O)₂R¹⁷; R¹⁷ and R¹⁸ have the same meaning as R⁵ and R⁶, definedabove; R^(F) is selected from: O, S and N(OR¹⁹); R¹⁹ has the samemeaning as R⁵, defined above; R^(G) is selected from: aryl, heteroaryl,and partially or fully saturated heterocycle, where said aryl,heteroaryl and heterocycle are substituted by one or more groups of theformula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) and optionally, further substituted byone or more groups selected from: —R⁵, halogen, —CN, —SCN, —CNO, —OR²¹,—OC(═O)R²¹, —OS(═O)₂R²¹, —OS(═O)₂NR²¹R²², —OC(═O)OR²¹, —OC(═O)SR²¹,—OC(═O)NR²¹R²², —SR²¹, —S(═O)R²¹, —NO₂, —NR²¹(OR²²), —NR²¹R²²,—NR²¹C(═O)R²², —N(R²¹)C(═O)OR²², —N[S(═O)₂R²¹]R²³, C(═O)OR²¹, —S(═O)₂R²¹and —S(═O)₂OR²¹; R²¹ has the same meaning as R¹, defined above, and R²is selected from: H, hydroxy, alkyl, partially or fully fluorinatedalkyl, alkoxy, alkenyl, alkynyl, carboxy, —C(═O)OR⁵, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl and heterocycle: T is selected from:—CH₂, O, S and NH; q is 0, 1, 2 or 3; R²³ and R²⁴ are independentlyselected from: H, alkyl alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heterocycle and C(═O)R²⁵, wherein said alkyl andalkenyl optionally contain at least one hetero atom selected from: O, Sand N, in any position of the alkyl or alkenyl chain, and said alkyl andalkenyl are unsubstituted or substituted with at least one groupselected from: —OR¹, —OC(═O)R¹, —OS(═O)₂R¹, —S(═O)₂NR¹R², —OC(═O)OR¹,—OC(═O)SR¹, —OC(═O)NR¹R², —SR¹, —S(═O)R¹, —SC(═O)H, —SC(═O)OR¹, —NR¹(OR²), —NR¹R², —NR¹C(═O)R², —N(R¹)C(═O)OR², —NR¹S(═O)₂R², C(═O)OR¹,—S(═O)₂R¹ and —S(═O)₂OR¹; R²⁵ is selected from: OR⁵, SR⁵, —OCR³R⁴ and—NR⁵R⁶, wherein R³, R⁴, R⁵ and R⁶ are as defined above and whereinoptionally, R³ and R⁴, together with the carbon to which they areattached, form an unsubstituted or substituted 5-, 6- or 7-memberedsaturated, partially saturated or aromatic heterocycle having one ormore heteroatoms selected from: N, O and S, wherein the substituents areselected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo,carboxy and —C(═O)OR⁵; and the group NR⁵R⁶ is, optionally, a heterocyclecontaining at least one additional heteroatom selected from: O, S, andN.
 9. The method according to claim 8, wherein in the compounds offormula (I) R^(G) is selected from: phenyl, piperidinyl and piperazinyl,and said phenyl, piperidinyl and piperazinyl are substituted by one ormore groups of the formula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) and optionally, further substituted byone or more groups selected from: —R⁵, halogen, —CN, —SCN, —CNO, —OR²¹,—OC(═O)R²¹, —OS(═O)₂R²¹, —OS(═O)₂NR²¹R²², —OC(═O)OR²¹, —OC(═O)SR²¹,—OC(═O)NR²¹R²², —SR²¹, S(═O)R²¹, —NO₂, —NR²¹(OR²²), —NR²¹R²²,—NR²¹C(═O)R²², N(R²¹)C(═O)OR²², —N[S(═O)₂R²¹]R²³, C(═O)OR²¹, —S(═O)₂R²¹and —S(═O)₂OR²¹; and R²¹ and R²² are as defined in claim
 8. 10. Themethod according to claim 8, wherein in the compounds of formula (I), R₁is hydrogen; R₃ and R₄ are independently selected from: H, OH, —C(O)OHand —C(O)Oalkyl; R^(B)═R^(C)═R^(D)═R^(E)=hydrogen; Y¹ and Y², togetherare ═O; n is the integer 0 or 1; R^(G) is phenyl, substituted with oneor more of the group of formula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) wherein R²³ is H and R²⁴ is H, and,optionally, the compound is further substituted with one or more of thegroups selected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl,oxo, carboxy, —C(═O)OR⁵, SR²¹, S(═O)₂R²¹ and —N(R²¹)—C(O)CH₃,—CH₂C(O)R²⁵; and R²⁵ is selected from: OR⁵, OCR³R⁴ and NR⁵R⁶, wherein R³and R⁴, together with the carbon to which they are attached form anunsubstituted or substituted 5-, 6- or 7-membered saturated, partiallysaturated or aromatic heterocycle having one or more heteroatomsselected from: N, O and S, wherein the substituents are selected from:hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy,—C(═O)OR⁵; and R⁵, R⁶ and R²¹ are independently selected from: H, alkyland phenyl.
 11. The method according to claim 8, wherein in thecompounds of formula (I), R₁ is hydrogen; R₃ and R₄ are independentlyselected from: H, OH, —C(O)OH and —C(O)Oalkyl;R^(B)═R^(C)═R^(D)═R^(E)=hydrogen; Y¹ and Y², together are ═O; n is theinteger 0 or 1; R^(G) is selected from: piperidinyl and piperazinyl,wherein said piperidinyl and piperazinyl are substituted with one ormore of the group of formula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) wherein R²³ is H and R²⁴ is H and,optionally, further substituted with one or more groups selected from:hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy and—C(═O)OR⁵; and R²⁵ is OR⁵, wherein R⁵ is selected from: H, alkyl andphenyl.
 12. The method according to claim 8, wherein the compounds offormula (I) are selected from the group consisting of:(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;4-(2-{5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl}-acetyl]-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methanesulfonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethoxycarbonyl methoxy-phenoxy)-acetic acid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(imino-{3-methyl-butyrylamino}-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-1-hydroxyimino-ethyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isobutoxycarbonyl methoxy-phenoxy)-acetic acid isobutyl ester;2-(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-N,N-diethyl-acetamide;4-(2-{4-[2-(5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylicacid benzyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenylsulfanyl)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-chloro-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethylsulfanyl-phenoxy)-acetic acid ethyl ester;(2-Ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethanesulfonyl-phenoxy)-acetic acid ethyl ester;(2-Ethanesulfonyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2,6-Bis-ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Acetylamino-4-{2-[5-N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-methoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-propoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxycarbonylmethoxy-phenoxy)-acetic acid ethyl ester;(3-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(2-Ethylsulfanyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(5-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isopropyl-phenoxy)-aceticacid ethyl ester;(2-tert-Butyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid benzyl ester;(2-Ethyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid;(4-Hydroxy-3-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-5-methoxy-phenoxy)-aceticacid ethyl ester;(3,5-Dihydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceicacid ethyl ester;(2-Ethoxycarbonylmethoxy-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(1-{2S-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-hydroxy-phenyl)-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{3-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(5-Methyl-isoxazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(tert-Butoxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid;(3-Ethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-[2-(5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-3-ethoxy-phenoxy}-aceticacid ethyl ester;(4-{2-[5-Carbamimdoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy-phenoxy)-aceticacid;(3-Hydroxy-4-{2-[1-oxo-5-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(Acetylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Acetoxy-4-{2-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid; and(3-Allyloxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester.
 13. The method according to claim 10, wherein thecompounds of formula (I) are selected from the group consisting of(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;4-(2-{5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl}-acetyl]-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methanesulfonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethoxycarbonyl methoxy-phenoxy)-acetic acid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(imino-{3-methyl-butyrylamino}-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-1-hydroxyimino-ethyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isobutoxycarbonyl methoxy-phenoxy)-acetic acid isobutyl ester;2-(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-N,N-diethyl-acetamide;4-(2-{4-[2-(5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylicacid benzyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenylsulfanyl)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-chloro-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethylsulfanyl-phenoxy)-acetic acid ethyl ester;(2-Ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethanesulfonyl-phenoxy)-acetic acid ethyl ester;(2-Ethanesulfonyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2,6-Bis-ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Acetylamino-4-{2-[5-N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-methoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-propoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxycarbonylmethoxy-phenoxy)-acetic acid ethyl ester;(3-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(2-Ethylsulfanyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(5-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isopropyl-phenoxy)-aceticacid ethyl ester;(2-tert-Butyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid benzyl ester;(2-Ethyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid;(4-Hydroxy-3-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-5-methoxy-phenoxy)-aceticacid ethyl ester;(3,5-Dihydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceicacid ethyl ester;(2-Ethoxycarbonylmethoxy-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Ethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-[2-(5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-3-ethoxy-phenoxy}-aceticacid ethyl ester;(4-{2-[5-Carbamimdoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy-phenoxy)-aceticacid;(3-Hydroxy-4-{2-[1-oxo-5-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(Acetylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Acetoxy-4-{2-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid; and(3-Allyloxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]acetyl}-phenoxy)-aceticacid ethyl ester.
 14. The method according to claim 11, wherein thecompounds of formula (I) are selected from the group consisting of:(1-{2S-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-hydroxy-phenyl)-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{3-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(5-Methyl-isoxazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(tert-Butoxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester; and(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid.
 15. The method according to claim 8, wherein the cardiovascularand cerebrovascular thromboembolic diseases include: arterialthromboembolism, cerebral thromboembolism, cerebral arterial thrombosis,coronary thrombosis, deep vein thrombosis, diabetes-relatedthromboembolic disorders, sudden ischemic emergencies, myocardialinfarction, pulmonary thromboembolisms, stroke, thrombophlebitis,transient ischemic attack, unstable angina and venous thrombosis orkidney thromboembolism.
 16. A method of inhibiting aggregation of bloodplatelet in a subject in need thereof, which comprises administering tothe subject a therapeutically effective amount of compound of generalformula (I); or a stereoisomer, a tautomer or a pharmaceuticallyacceptable salt thereof;

wherein ring A is phenyl; R^(A) is a group of formula (3):

wherein p is 0; s is 1; R¹ is selected from: H, hydroxy, alkyl,partially or fully fluorinated alkyl, alkoxy, alkenyl, alkynyl, carboxy,—C(═O)OR⁵, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle;R³ and R⁴ are independently selected from: H, alkyl, partially or fullyfluorinated alkyl, alkenyl, alkynyl, —C(═O)OR⁵, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycle, —OR⁵—SR⁵, —NR⁵R⁶,—S(═O)₂NR⁵R⁶, —S(═O)₂R⁵, —C(═O)R⁵, —C(═O)NR⁵R⁶, —C(═O)OR⁵, —C(═O)SR⁵,—OC(═O)R⁵, —OC(═O)OR⁵, —OC(═O)NR⁵R⁶, —OS(═O)₂R⁵, —S(C═O)NR⁵ and—OS(═O)₂NR⁵R⁶, or R³ and R¹ or R⁴, together with the respective nitrogenatoms to which they are attached, form an unsubstituted or substituted5-, 6- or 7-membered partially saturated or aromatic heterocycle,optionally having one or more additional heteroatoms selected from: N, Oand S, wherein the substituents are selected from: hydroxy, halogen,alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy and —C(═O)OR⁵; R⁵ and R⁶are independently selected from: H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl and heterocycle, wherein each of saidalkyl, alkenyl, alkynyl, cycloalkyl and cycloalkylalkyl group optionallycontains at least one hetero atom selected from: N, S and O anywhere inthe chain, including the terminal position; R^(B) is H; Y¹ and Y²,together, are selected from: ═O and ═S; Z is N; W is CH; R^(C) is H; nis 0, 1, 2 or 3; R^(D) and R^(E) are independently selected from: H andan unsubstituted or substituted group selected from: alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle,wherein the substituents are selected from: hydroxy, halogen, alkyl,alkenyl, alkynyl, oxo, carboxy, —C(═O)OR⁵, —OR¹⁷, —SR¹⁷, —NR¹⁷R¹⁸,—NHC(═O)R¹⁷, —NHC(═O)OR¹⁷, —OC(═O)R¹⁷, —SC(═O)R¹⁷, —OS(═O)₂R¹⁷ and—NHS(═O)₂R¹⁷; R¹⁷ and R¹⁸ have the same meaning as R⁵ and R⁶, definedabove; R^(F) is selected from: O, S and N(OR¹⁹); R¹⁹ has the samemeaning as R⁵, defined above; R^(G) is selected from: aryl, heteroaryl,and partially or fully saturated heterocycle, where said aryl,heteroaryl and heterocycle are substituted by one or more groups of theformula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) and optionally, further substituted byone or more groups selected from: —R⁵, halogen, —CN, —SCN, —CNO, —OR²¹,—OC(═O)R²¹, —OS(═O)₂R²¹, —OS(═O)₂NR²¹R²², —OC(═O)OR²¹, —OC(═O)SR²¹,—OC(═O)NR²¹R²², —SR²¹, —S(═O)R²¹, —NO₂, —NR²¹(OR²²), —NR²¹R²²,—NR²¹C(═O)R²², —N(R²¹)C(═O)OR²², —N[S(═O)₂R²¹]R²³, C(═O)OR²¹, —S(═O)₂R²¹and —S(═O)₂OR²¹; R²¹ has the same meaning as R¹, defined above, and R²is selected from: H, hydroxy, alkyl, partially or fully fluorinatedalkyl, alkoxy, alkenyl, alkynyl, carboxy, —C(═O)OR⁵, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl and heterocycle: T is selected from:—CH₂, O, S and NH; q is 0, 1, 2 or 3; R²³ and R²⁴ are independentlyselected from: H, alkyl alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heterocycle and C(═O)R²⁵, wherein said alkyl andalkenyl optionally contain at least one hetero atom selected from: O, Sand N, in any position of the alkyl or alkenyl chain, and said alkyl andalkenyl are unsubstituted or substituted with at least one groupselected from: —OR¹, —OC(═O)R¹, —OS(═O)₂R¹, —S(═O)₂NR¹R², —OC(═O)OR¹,—OC(═O)SR¹, —OC(═O)NR¹R², —SR¹, —S(═O)R¹, —SC(═O)H, —SC(═O)OR¹,—NR¹(OR²), —NR¹R², —NR¹C(═O)R², —N(R¹)C(═O)OR², —NR¹S(═O)₂R², C(═O)OR¹,—S(═O)₂R¹ and —S(═O)₂OR¹; R²⁵ is selected from: OR⁵, SR⁵, —OCR³R⁴ and—NR⁵R⁶, wherein R³, R⁴, R⁵ and R⁶ are as defined above and whereinoptionally, R³ and R⁴, together with the carbon to which they areattached, form an unsubstituted or substituted 5-, 6- or 7-memberedsaturated, partially saturated or aromatic heterocycle having one ormore heteroatoms selected from: N, O and S, wherein the substituents areselected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo,carboxy and —C(═O)OR⁵; and the group NR⁵R⁶ is, optionally, a heterocyclecontaining at least one additional heteroatom selected from: O, S, andN.
 17. The method according to claim 16, wherein in the compounds offormula (I); R^(G) is selected from: phenyl, piperidinyl andpiperazinyl, and said phenyl, piperidinyl and piperazinyl aresubstituted by one or more groups of the formula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) and optionally, further substituted byone or more groups selected from: —R⁵, halogen, —CN, —SCN, —CNO, —OR²¹,—OC(═O)R²¹, —OS(═O)₂R²¹, —OS(═O)₂NR²¹R²², —OC(═O)OR²¹, —OC(═O)SR²¹,—OC(═O)NR²¹R²², —SR²¹, —S(═O)R²¹, —NO₂, —NR²¹(OR²²), —NR²¹R²²,—NR²¹C(═O)OR²², —N(R²¹)C(═O)OR²², —N[S(═O)₂R²¹]R²³, C(═O)OR²¹,—S(═O)₂R²¹, and —S(═O)₂OR²¹; and R²¹ and R²² are as defined in claim 16.18. The method according to claim 16, wherein in the compounds offormula (I); R₁ is hydrogen; R₃ and R₄ are independently selected from:H, OH, —C(O)OH and —C(O)Oalkyl; R^(B)═R^(C)═R^(D)═R^(E)=hydrogen; Y¹ andY², together are ═O; n is the integer 0 or 1; R^(G) is phenyl,substituted with one or more of the group of formula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) wherein R²³ is H and R²⁴ is H, and,optionally, the compound is further substituted with one or more of thegroups selected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl,oxo, carboxy, —C(═O)OR⁵, SR²¹, S(═O)₂R²¹ and —N(R²¹)—C(O)CH₃,—CH₂C(O)R²⁵; and R²⁵ is selected from: OR⁵, OCR³R⁴ and NR⁵R⁶, wherein R³and R⁴, together with the carbon to which they are attached form anunsubstituted or substituted 5-, 6- or 7-membered saturated, partiallysaturated or aromatic heterocycle having one or more heteroatomsselected from: N, O and S, wherein the substituents are selected from:hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy,—C(═O)OR⁵; and R⁵, R⁶ and R²¹ are independently selected from: H, alkyland phenyl.
 19. The method according to claim 16, wherein in thecompounds of formula (I) R₁ is hydrogen; R₃ and R₄ are independentlyselected from: H, OH, —C(O)OH and —C(O)Oalkyl;R^(B)═R^(C)═R^(D)═R^(E)=hydrogen; Y¹ and Y², together are ═O; n is theinteger 0 or 1; R^(G) is selected from: piperidinyl and piperazinyl,wherein said piperidinyl and piperazinyl are substituted with one ormore of the group of formula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) wherein R²³ is H and R²⁴ is H and,optionally, further substituted with one or more groups selected from:hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy and—C(═O)OR⁵; and R²⁵ is OR⁵, wherein R⁵ is selected from: H, alkyl andphenyl.
 20. The method according to claim 16, wherein the compounds offormula (I) are selected from the group consisting of:(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;4-(2-{5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl}-acetyl]-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methanesulfonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethoxycarbonyl methoxy-phenoxy)-acetic acid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(imino-{3-methyl-butyrylamino}-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-1-hydroxyimino-ethyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isobutoxycarbonyl methoxy-phenoxy)-acetic acid isobutyl ester;2-(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-N,N-diethyl-acetamide;4-(2-{4-[2-(5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylicacid benzyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenylsulfanyl)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-chloro-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethylsulfanyl-phenoxy)-acetic acid ethyl ester;(2-Ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethanesulfonyl-phenoxy)-acetic acid ethyl ester;(2-Ethanesulfonyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2,6-Bis-ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Acetylamino-4-{2-[5-N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-methoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-propoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxycarbonylmethoxy-phenoxy)-acetic acid ethyl ester;(3-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(2-Ethylsulfanyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(5-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isopropyl-phenoxy)-aceticacid ethyl ester;(2-tert-Butyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid benzyl ester;(2-Ethyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid;(4-Hydroxy-3-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-5-methoxy-phenoxy)-aceticacid ethyl ester;(3,5-Dihydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceicacid ethyl ester;(2-Ethoxycarbonylmethoxy-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(1-{2S-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-hydroxy-phenyl)-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{3-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(5-Methyl-isoxazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(tert-Butoxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid;(3-Ethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-[2-(5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-3-ethoxy-phenoxy}-aceticacid ethyl ester;(4-{2-[5-Carbamimdoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy-phenoxy)-aceticacid;(3-Hydroxy-4-{2-[1-oxo-5-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(Acetylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Acetoxy-4-{2-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid; and(3-Allyloxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]acetyl}-phenoxy)-aceticacid ethyl ester.
 21. The method according to claim 18, wherein thecompounds of formula (I) are selected from the group consisting of:(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;4-(2-{5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl}-acetyl]-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methanesulfonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethoxycarbonyl methoxy-phenoxy)-acetic acid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(imino-{3-methyl-butyrylamino}-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-1-hydroxyimino-ethyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isobutoxycarbonyl methoxy-phenoxy)-acetic acid isobutyl ester;2-(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]acetyl}-phenoxy)-N,N-diethyl-acetamide;4-(2-{4-[2-(5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylicacid benzyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenylsulfanyl)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-chloro-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethylsulfanyl-phenoxy)-acetic acid ethyl ester;(2-Ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethanesulfonyl-phenoxy)-acetic acid ethyl ester;(2-Ethanesulfonyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2,6-Bis-ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Acetylamino-4-{2-[5-N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-methoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-propoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxycarbonylmethoxy-phenoxy)-acetic acid ethyl ester;(3-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(2-Ethylsulfanyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(5-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isopropyl-phenoxy)-aceticacid ethyl ester;(2-tert-Butyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid benzyl ester;(2-Ethyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid;(4-Hydroxy-3-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-5-methoxy-phenoxy)-aceticacid ethyl ester;(3,5-Dihydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceicacid ethyl ester;(2-Ethoxycarbonylmethoxy-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Ethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-[2-(5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-3-ethoxy-phenoxy}-aceticacid ethyl ester;(4-{2-[5-Carbamimdoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy-phenoxy)-aceticacid;(3-Hydroxy-4-{2-[1-oxo-5-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(Acetylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Acetoxy-4-{2-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid; and(3-Allyloxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester.
 22. The method according to claim 19, wherein thecompounds of formula (I) are selected from the group consisting of:(1-{2S-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-hydroxy-phenyl)-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{3-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(5-Methyl-isoxazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(tert-Butoxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester; and(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid.
 23. The method according to claim 16, wherein the aggregation ofblood platelet include: platelet thrombosis, thromboembolism andreocclusion during and after thrombolytic therapy and plateletthrombosis, thromboembolism and reocclusion after angioplasty orcoronary artery bypass surgery, and blood clots after orthopedicsurgery.
 24. A method for the treatment of diseases involving a celladhesion process in a subject in need thereof, which comprisesadministering to the subject a therapeutically effective amount ofcompound of general formula (I); or a stereoisomer, a tautomer or apharmaceutically acceptable salt thereof;

wherein ring A is phenyl; R^(A) is a group of formula (3):

wherein p is 0; s is 1; R¹ is selected from: H, hydroxy, alkyl,partially or fully fluorinated alkyl, alkoxy, alkenyl, alkynyl, carboxy,—C(═O)OR⁵, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle;R³ and R⁴ are independently selected from: H, alkyl, partially or fullyfluorinated alkyl, alkenyl, alkynyl, —C(═O)OR⁵, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycle, —OR⁵, —SR⁵, —NR⁵R⁶,—S(═O)₂NR⁵R⁶, —S(═O)₂R⁵, —C(═O)R⁵, —C(═O)NR⁵R⁶, —C(═O)OR⁵, —C(═O)SR⁵,—OC(═O)R⁵, —OC(═O)OR⁵, —OC(═O)NR⁵R⁶, —OS(═O)₂R⁵, —S(C═O)NR⁵ and—OS(═O)₂NR⁵R⁶, or R³ and R¹ or R⁴, together with the respective nitrogenatoms to which they are attached, form an unsubstituted or substituted5-, 6- or 7-membered partially saturated or aromatic heterocycle,optionally having one or more additional heteroatoms selected from: N, Oand S, wherein the substituents are selected from: hydroxy, halogen,alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy and —C(═O)OR⁵; R⁵ and R⁶are independently selected from: H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl and heterocycle, wherein each of saidalkyl, alkenyl, alkynyl, cycloalkyl and cycloalkylalkyl group optionallycontains at least one hetero atom selected from: N, S and O anywhere inthe chain, including the terminal position; R^(B) is H; Y¹ and Y²,together, are selected from: ═O and ═S; Z is N; W is CH; R^(C) is H; nis 0, 1, 2 or 3; R^(D) and R^(E) are independently selected from: H andan unsubstituted or substituted group selected from: alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle,wherein the substituents are selected from: hydroxy, halogen, alkyl,alkenyl, alkynyl, oxo, carboxy, —C(═O)OR⁵, —OR¹⁷, —SR¹⁷, —NR¹⁷R¹⁸,—NHC(═O)R¹⁷, —NHC(═O)OR¹⁷, —OC(═O)R¹⁷, —SC(═O)R¹⁷, —OS(═O)₂R¹⁷ and—NHS(═O)₂R¹⁷; R¹⁷ and R¹⁸ have the same meaning as R⁵ and R⁶, definedabove; R^(E) is selected from: O, S and N(OR¹⁹); R¹⁹ has the samemeaning as R⁵, defined above; R^(G) is selected from: aryl, heteroaryl,and partially or fully saturated heterocycle, where said aryl,heteroaryl and heterocycle are substituted by one or more groups of theformula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) and optionally, further substituted byone or more groups selected from: —R⁵, halogen, —CN, —SCN, —CNO, —OR²¹,—OC(═O)R²¹, —OS(═O)₂R²¹, —OS(═O)₂NR²¹R²², —OC(═O)OR²¹, —OC(═O)SR²¹,—OC(═O)NR²¹R²², —SR²¹, —S(═O)R²¹, —NO₂, —NR²¹(OR²²), —NR²¹R²²,—NR²¹C(═O)R²², —N(R²¹)C(═O)OR²², —N[S(═O)₂R²¹]R²³, C(═O)OR²¹, —S(═O)₂R²¹and —S(═O)₂OR²¹; R²¹ has the same meaning as R¹, defined above, and R²is selected from: H, hydroxy, alkyl, partially or fully fluorinatedalkyl, alkoxy, alkenyl, alkynyl, carboxy, —C(═O)OR⁵, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl and heterocycle: T is selected from:—CH₂, O, S and NH; q is 0, 1, 2 or 3; R²³ and R²⁴ are independentlyselected from: H, alkyl alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heterocycle and C(═O)R²⁵, wherein said alkyl andalkenyl optionally contain at least one hetero atom selected from: O, Sand N, in any position of the alkyl or alkenyl chain, and said alkyl andalkenyl are unsubstituted or substituted with at least one groupselected from: —OR¹, —OC(═O)R¹, —OS(═O)₂R¹, —S(═O)₂NR¹R², —OC(═O)OR¹,—OC(═O)SR¹, —OC(═O)NR¹R², —SR¹, —S(═O)R¹, —SC(═O)H, —SC(═O)OR¹,—NR¹(OR²), —NR¹R², —NR¹C(═O)R², —N(R¹)C(═O)OR², —NR¹S(═O)₂R², C(═O)OR¹,—S(═O)₂R¹ and —S(═O)₂OR¹; R²⁵ is selected from: OR⁵, SR⁵, —OCR³R⁴ and—NR⁵R⁶, wherein R³, R⁴, R⁵ and R⁶ are as defined above and whereinoptionally, R³ and R⁴, together with the carbon to which they areattached, form an unsubstituted or substituted 5-, 6- or 7-memberedsaturated, partially saturated or aromatic heterocycle having one ormore heteroatoms selected from: N, O and S, wherein the substituents areselected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo,carboxy and —C(═O)OR⁵; and the group NR⁵R⁶ is, optionally, a heterocyclecontaining at least one additional heteroatom selected from: O, S, andN.
 25. The method according to claim 24, wherein in the compounds offormula (I); R^(G) is selected from: phenyl, piperidinyl andpiperazinyl, and said phenyl, piperidinyl and piperazinyl aresubstituted by one or more groups of the formula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) and optionally, further substituted byone or more groups selected from: —R⁵, halogen, —CN, —SCN, —CNO, —OR²¹,—OC(═O)R²¹, —OS(═O)₂R²¹, —OS(═O)₂NR²¹R²², —OC(═O)OR²¹, —OC(═O)SR²¹,—OC(═O)NR²¹R²², —SR²¹, —S(═O)R²¹, —NO₂, —NR²¹(OR²²), —NR²¹R²²,—NR²¹C(═O)R²², —N(R²¹)C(═O)OR²², —N[S(═O)₂R²¹]R²³, C(═O)OR²¹, —S(═O)₂R²¹and —S(═O)₂OR²¹; and R²¹ and R²² are as defined in claim
 24. 26. Themethod according to claim 24, wherein in the compounds of formula (I);R₁ is hydrogen; R₃ and R₄ are independently selected from: H, OH,—C(O)OH and —C(O)Oalkyl; R^(B)═R^(C)═R^(D)═R^(E)=hydrogen; Y¹ and Y²,together are ═O; n is the integer 0 or 1; R^(G) is phenyl, substitutedwith one or more of the group of formula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) wherein R²³ is H and R²⁴ is H, and,optionally, the compound is further substituted with one or more of thegroups selected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl,oxo, carboxy, —C(═O)OR⁵, SR²¹, S(═O)₂R²¹ and —N(R²¹)—C(O)CH₃,—CH₂C(O)R²⁵; and R²⁵ is selected from: OR⁵, OCR³R⁴ and NR⁵R⁶, wherein R³and R⁴, together with the carbon to which they are attached form anunsubstituted or substituted 5-, 6- or 7-membered saturated, partiallysaturated or aromatic heterocycle having one or more heteroatomsselected from: N, O and S, wherein the substituents are selected from:hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy,—C(═O)OR⁵; and R⁵, R⁶ and R²¹ are independently selected from: H, alkyland phenyl.
 27. The method according to claim 24, wherein in thecompounds of formula (I); R₁ is hydrogen; R₃ and R₄ are independentlyselected from: H, OH, —C(O)OH and —C(O)Oalkyl;R^(B)═R^(C)═R^(D)═R^(E)=hydrogen; Y¹ and Y², together are ═O; n is theinteger 0 or 1; R^(G) is selected from: piperidinyl and piperazinyl,wherein said piperidinyl and piperazinyl are substituted with one ormore of the group of formula (5):T-(CH₂)_(q)—CR²³R²⁴—COR²⁵  (5) wherein R²³ is H and R²⁴ is H and,optionally, further substituted with one or more groups selected from:hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy and—C(═O)OR⁵; and R²⁵ is OR⁵, wherein R⁵ is selected from: H, alkyl andphenyl.
 28. The method according to claim 24, wherein the compounds offormula (I) are selected from the group consisting of:(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;4-(2-{5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl}-acetyl]-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methanesulfonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethoxycarbonyl methoxy-phenoxy)-acetic acid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(imino-{3-methyl-butyrylamino}-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-1-hydroxyimino-ethyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isobutoxycarbonyl methoxy-phenoxy)-acetic acid isobutyl ester;2-(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-N,N-diethyl-acetamide;4-(2-{4-[2-(5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylicacid benzyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenylsulfanyl)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-chloro-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethylsulfanyl-phenoxy)-acetic acid ethyl ester;(2-Ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethanesulfonyl-phenoxy)-acetic acid ethyl ester;(2-Ethanesulfonyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2,6-Bis-ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Acetylamino-4-{2-[5-N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-methoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-propoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxycarbonylmethoxy-phenoxy)-acetic acid ethyl ester;(3-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(2-Ethylsulfanyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(5-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isopropyl-phenoxy)-aceticacid ethyl ester;(2-tent-Butyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid benzyl ester;(2-Ethyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid;(4-Hydroxy-3-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-5-methoxy-phenoxy)-aceticacid ethyl ester;(3,5-Dihydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceicacid ethyl ester;(2-Ethoxycarbonylmethoxy-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(1-{2S-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-hydroxy-phenyl)-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{3-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(5-Methyl-isoxazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(tert-Butoxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid;(3-Ethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-[2-(5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-3-ethoxy-phenoxy}-aceticacid ethyl ester;(4-{2-[5-Carbamimdoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy-phenoxy)-aceticacid;(3-Hydroxy-4-{2-[1-oxo-5-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-1,3-dihydro-isoindol-2-yl]acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(Acetylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Acetoxy-4-{2-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid; and(3-Allyloxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester.
 29. The method according to claim 26, wherein thecompounds of formula (I) are selected from the group consisting of:(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;4-(2-{5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl}-acetyl]-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isopropyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(Imino-methanesulfonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid isobutyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethoxycarbonyl methoxy-phenoxy)-acetic acid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(imino-{3-methyl-butyrylamino}-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-1-hydroxyimino-ethyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isobutoxycarbonyl methoxy-phenoxy)-acetic acid isobutyl ester;2-(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-N,N-diethyl-acetamide;4-(2-{4-[2-(5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylicacid benzyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;4-Benzyloxycarbonylamino-2-(4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyricacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenylsulfanyl)-aceticacid methyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-chloro-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethylsulfanyl-phenoxy)-acetic acid ethyl ester;(2-Ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethanesulfonyl-phenoxy)-acetic acid ethyl ester;(2-Ethanesulfonyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2,6-Bis-ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Acetylamino-4-{2-[5-N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-methoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-propoxy-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxycarbonylmethoxy-phenoxy)-acetic acid ethyl ester;(3-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid;(2-Ethylsulfanyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(5-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isopropyl-phenoxy)-aceticacid ethyl ester;(2-tert-Butyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Chloro-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-aceticacid benzyl ester;(2-Ethyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid benzyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid;(4-Hydroxy-3-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-5-methoxy-phenoxy)-aceticacid ethyl ester;(3,5-Dihydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(2-Ethoxycarbonylmethoxy-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceicacid ethyl ester;(2-Ethoxycarbonylmethoxy-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(3-Ethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-[2-(5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-3-ethoxy-phenoxy}-aceticacid ethyl ester;(4-{2-[5-Carbamimdoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy-phenoxy)-aceticacid;(3-Hydroxy-4-{2-[1-oxo-5-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-(Acetylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-aceticacid ethyl ester;(3-Acetoxy-4-{2-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester;(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-aceticacid ethyl ester;(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-aceticacid; and(3-Allyloxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-aceticacid ethyl ester.
 30. The method according to claim 27, wherein thecompounds of formula (I) are selected from the group consisting of:(1-{2S-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-hydroxy-phenyl)-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{3-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(5-Methyl-isoxazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester;(1-{2-[5-(tert-Butoxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid ethyl ester; and(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-aceticacid.
 31. The method according to claim 24, wherein the diseasesinvolving a cell adhesion process include: adult respiratory distresssyndrome, allergies, asthma, rupture of atherosclerotic plaques,autoimmune diseases, inflammation, bone degradation, contact dermatitis,diabetic retinopathy, eczema, graft versus host disease, inflammatorybowel disease, metastasis, organ transplantation rejection,osteoarthritis, osteoporosis, psoriasis, rheumatoid arthritis, septicshock and tumors.